帕金森病多巴胺能神经元轴突变性新的体外实验细胞模型的建立及机制研究
|
摘要
帕金森病是(Parkinson’ disease,PD)中枢神经系统常见的进行性、变性性疾病，黑质多巴胺能(Dopaminergic,DAG)神经元选择性的凋亡目前被认为是PD的主要病理变化，既往的重点主要集中在对DAG神经元凋亡机制的研究和治疗方面，而轴突变性被认为是神经元死亡后的伴随产物，因此一直未受到重视。但近年来的研究发现，单纯抑制神经元凋亡并不能有效延缓PD的发生和发展，而DAG轴突变性可能是PD发病的一个重要原因和靶点。尽管现在已经逐渐认识到PD中轴突变性的重要性，但是对于轴突变性在PD中的作用和机制，目前还缺乏了解，因此对轴突变性在PD中的作用和机制的研究不仅可以为PD发病机制的理解带来理论革新，还可为我们治疗PD提供新的策略和靶点，具有重大的理论和现实意义。
第一部分：一个新的帕金森病多巴胺能神经元轴突变性体外实验细胞模型的建立
目的：利用1-甲基-4-苯基吡啶离子(MPP~+)对小鼠胚胎中脑多巴胺能神经元的毒性作用，建立一个新的PD多巴胺能神经元轴突变性体外实验细胞模型。方法：采用C57BL/6小鼠胚胎(孕14d)中脑腹侧组织进行原代细胞培养，实验分为对照组和不同浓度(0.1、0.5、1.0、10.0μM) MPP~+药物实验组，应用酪氨酸羟化酶(TH)免疫荧光化学细胞染色方法对DAG神经元损伤的形态学进行观察，对DAG神经元数量、轴突数目和长度分别在2、4、6、8、12、24h共6个时间点进行研究。TUNEL检测细胞凋亡情况。结果：MPP~+作用于DAG神经元后细胞数量减少，绝大多数表现为胞体存在，轴突的数目及长度明显减少，网状交织的轴突变得稀疏，表面不光滑，有的呈串珠样肿胀或轴突中断，少数表现为胞体空虚、丢失，仅有轴突存在。DAG神经元细胞数量、轴突长度、轴突数目的减少，对MPP~+有时间-剂量依赖性。分析数据发现只有10.0μM MPP~+作用DAG神经元24小时组在神经元数量、轴突长度、轴突数目这三个方面与其余各组之间比较有显著性差异(P<0.05)。此时，对照组DAG神经元的数量、轴突长度、轴突数目分别为(254±11)个/孔、(158.99±12.13)μm/个、(1.82±0.30)个，MPP~+实验组为(126±16)个/孔、(64.18±19.06) μm/个、(1.17±0.35)个。DAG神经元数量减少了50.39%，每个DAG神经元轴突长度减少了59.8%，每个DAG神经元的轴突数目减少35.7%。TUNEL检测10.0μM MPP~+作用DAG神经元24小时后DAG神经元以凋亡为主，占丢失细胞总数的90.7%。结论:0.1、0.5、1.0、10.0μM MPP~+均能引起DAG神经元损伤，形态改变、数量减少、轴突长度变短、数目减少。而以10.0μM MPP~+作用多巴胺能神经元24小时造模最为理想。
第二部分:帕金森病多巴胺能神经元轴突变性指标的检测
目的：观察淀粉样前体蛋白(APP)和微管蛋白β-TubulinⅢ在MPP~+作用DAG神经元后表达的变化情况，从轴浆运输障碍、微管出现解聚两方面来验证MPP~+诱导的DAG神经元轴突发生了变性。方法：分MPP~+实验组和对照组。细胞培养7天后，实验组应用10.0μM MPP~+作用24h，对照组不予任何干预。TH-APP免疫荧光双标来检测DAG神经元APP的表达。Weston-blot检测细胞β-TubulinⅢ的表达变化。MPP~+实验组使用含有洗脱剂的4%多聚甲醛固定，洗出游离的微管蛋白，检测细胞聚合状态的微管蛋白。对照组使用4%多聚甲醛固定，检测细胞总的微管蛋白。结果：对照组DAG神经元及轴突形态正常， APP呈低表达。MPP~+作用后DAG神经元轴突出现片段化，APP表达升高，在轴突中可见APP局部浓集。Weston-blot检测细胞β-TubulinⅢ的表达，对照组平均灰度值比值为10.08±0.6，实验组为4.36±0.3，与对照组相比实验组下降了56.75%。结论：10.0μM MPP~+作用DAG神经元24h，出现了轴浆运输障碍及轴突微管解聚现象，轴突发生了变性。
第三部分:帕金森病多巴胺能神经元轴突变性相关信号通路的研究
目的：探讨PI3-kinase/Akt/GSK-3β和Rho/ROCK信号通路可能参与了MPP~+诱导的DAG神经元轴突变性。方法：在已建立的细胞模型中使用GSK-3β抑制剂LiCl和ROCK抑制剂Fasudil。LiCl作用浓度为5、10、20、30μM，Fasudil作用浓度为25、50、100、150μM。研究分对照组和实验组。对照组细胞培养7天后，应用10.0μMMPP~+作用24h。实验组细胞培养7天后，应用10.0μM MPP~++不同浓度LiCl或10.0Μm MPP~++不同浓度Fasudil作用24h。TH免疫荧光染色观察轴突长度、轴突数目；实验组将有抑制作用浓度的LiCl、Fasudil组使用洗脱剂和对照组使用洗脱剂洗去游离的微管蛋白，用Weston-blot检测细胞聚合状态β-TubulinⅢ的表达。结果：①对照组轴突长度为(88.45±17.12)μm，实验组5、10、20、30μM LiCl作用后轴突长度分别为(119.03±25.19)、(115.92±20.10)、(97.21±15.58)、(88.31±16.26)μm。5、10μMLiCl组与对照组相比有显著性差异(P<0.05)，20、30μM LiCl组与对照组相比无显著性差异(P＞0.05)。而5和10μM LiCl组、20和30μM LiCl组间无显著性差异(P＞0.05)。对照组轴突数目为(1.56±0.32)个，实验组5、10、20、30μM LiCl作用后轴突长度分别为(1.75±0.41)、(1.66±0.33)、(1.65±0.30)、(1.64±0.38)个，与对照组相比各浓度LiCl组无显著性差异(P＞0.05)。②对照组轴突长度为(86.34±16.18)μm，实验组25、50、100、150μM Fasudil作用后轴突长度分别为(95.97±20.67)、(118.30±19.11)、(132.39±26.95)、（87.01±25.89）μm。50、100μM Fasudil组与对照组相比有显著性差异(P<0.05)，25、150μMFasudil组与对照组相比无显著性差异(P＞0.05)。而50和100μMFasudil组、25和150μMFasudil组间无显著性差异(P＞0.05)。对照组轴突数目为(1.55±0.29)个，实验组25、50、100、150μM Fasudil作用后轴突数目分别为(1.69±0.43)、(1.65±0.35)、(1.53±0.38)、(1.57±0.50)个，与对照组相比各浓度Fasudil组无显著性差异(P＞0.05)。Weston-blot检测细胞β-TubulinⅢ：③LiCl组实验结果显示：平均灰度值比值5μM LiCl组为5.68±0.29，10μM LiCl组为5.35±0.22，对照组为3.56±0.14，实验组与对照组有显著性差异(p＜0.05)，实验组之间无显著性差异（P＞0.05）。5、10μM LiCl作用后聚合状态β-TubulinⅢ的表达增高，其抑制了变性DAG轴突微管蛋白的解聚。④Fasudil组实验结果显示：平均灰度值比值50μM Fasudil组为4.61±0.32，100μMFasudil组为4.45±0.21，对照组为2.76±0.16，实验组与对照组有显著性差异(p＜0.05)，实验组之间无显著性差异(P＞0.05)。50、100μM Fasudil作用后聚合状态β-TubulinⅢ的表达增高，其抑制了变性DAG轴突微管蛋白的解聚。结论：PI3-kinase/Akt/GSK-3β和Rho/ROCK信号通路参与了MPP~+诱导的DAG神经元轴突变性。 LiCl、Fasudil在合适的浓度可以发挥信号通路抑制作用而保护了变性的DAG神经元轴突。
Parkinson’s disease(PD) is a common progressive and neurodegenerativedisease in central nervous system.The primary pathology of PD is selective lossof dopaminergic neurons in the substantia nigra pars compacta.Previous studiesmainly focused on the mechanisms of dopaminergic neurona apoptosis.Axonaldegeneration of dopaminergic neurons was thought to be accompanied withneurons’ loss for a long time.Recently,some findings have demonstrated thatsimply inhibiting process of dopaminergic neurons apotosis could not postponethe onset and development of PD efficiently. Dopaminergic axonal degenerationmight be a key feature and target for PD.Although we have been graduallyconvinced of the important role of axonal degeneration in PD, the mechanismsand the role of axonal degeneration remain unknown. And,we have little specialmethods to treat the axonal degeneration in PD.So the studying of mechanismsand the role of axonal degeneration in PD will not only bring us new theories,butalso bring us new strategies and target to treat PD.
Part1. Establishment of a new cell model of dopaminergic axonal degeneration for Parkinson’s disease in vitro
Objective To investigate dopaminergic axonal degeneration induced by MPP~+in mouse ventral mesencephalic culture and establish a new cell model for PDresearch in vitro. Methods C57BL/6mouse embroys of14d were used to makeventral mesencephalic dissociated culture. And it was divided into the control andMPP~+-treated groups. Different final concentrations (0.1,0.5,1.0and10.0μM) ofMPP~+were added into the MPP~+-treated groups on the7th day and then incubated.By application of anti-tyrosine hydroxylase (TH) monoclone antibodyimmunostaining, we observed morphology,axons length,axons number andamount of dopaminergic neurons at the time of2,4,6,8,12,24h. TUNEL was usedto identify the apoptotic dopaminergic neurons. Results Followed by MPP~+induced injury, TH-ir cells decreased and morphology changed obviously.Although most cell bodies existed, axons length and number decreased. Cellularinterlaced axons were sparse and unsmooth with a string of beads swelling orsegments. A few of TH-ir cells showed axon existed but cell body loss. Thesephenomena including TH-ir cells,axons length and number decreased,which weredependent on dose and time of MPP~+-treated. We found that decrease of cellamounts,axons length and number by10.0μM MPP~+for24h had statisticalsignificance. At this time, TH-ir cells, axons length and number was (254±11)/perwell,(158.99±12.13)μm/per cell,(1.82±0.30)/per cell in control groups,and(126±16)/per well,(64.18±19.06) μm/per cell,(1.17±0.35)/per cell in MPP~+-treated groups. TH-ir cells, axons length and number had decreased50.39%,59.8%,59.8%. Amount of apototic TH-ir cell accounted for90.7%in all losscells,which indicated that apotosis was the main mode of cells loss in thisexperiment system. Conclusion MPP~+with different final concentrations(0.1,0.5,1.0and10.0μM) could cause injury related morphological changs to TH-ir cells,axon length and number.It was the best method that10.0μM MPP~+treated dopaminergic neurons for24h for the model.
Part2. Identified dopaminergic axonal degeneration in Parkinson’s disease
Objective To study axon degeneration of MPP~+-treated dopaminergic neurons inPD by detecting amyloid precursor protein (APP)and microtube proteinβ-Tubulin Ⅲ to observe the fact ofaxonal transport defect and microtubedisassembled. Methods It was divided into control and MPP~+-treated groups.MPP~+with final concentration(10.0μM) were added into the MPP~+-treated groupson the7th day,and incubated for24h.Control groups were treated by nothing.Double staining with TH and APP immunofluorescence detected the expressionof APP in dopaminergic neurons. To detect the expression of β-TubulinⅢ in cellextracts, MPP~+-treated groups were fixed with4%paraformaldehyde whichcontained dehydranter (0.1M PB,10mM EGTA,2mM MgCl2,0.2%Triton X-100)to remove dissociative and left polymerization microtube protein.Controlgroups were fixed with4%paraformaldehyde only. Results TH-ir cells withlow expression of APP were normal in control groups. TH-ir axons with highexpression of APP,and APP local accumulation were segments in MPP~+-treatedgroups. Western-blot analysis showed polymerization microtube proteinβ-TubulinⅢ in cell extracts that mean density ratio of MPP~+-treated groups was4.36±0.3,and control groups was10.08±0.6, β-Tubulin Ⅲ expressionin cellextracts of MPP~+-treated groups was decreased56.75%than controlgroups.Conclusion10.0μM MPP~+treated for24h caused dopamineric axondegeneraton, axonal transport defect and microtube disassembled.
Part3. Exploring dopaminergic axonal degeneration associated signalpathways in Parkinson’s disease
Objective To explore dopaminergic axonal degeneration associated signal pathways in PD.Methods Final concentrations of GSK-3β inhibitor lithiumchloride(5、10、20、30μM) and ROCK inhibitor Fasudil (25、50、100、150μM)wereadministrated to the cell model that we had established. It was divided intocontrol and inhibitor-treated groups.10.0μMMPP~+treated the control groups onthe7th day,and incubated for24h.10.0μΜMPP~+and various final concentrationsLiCl or Fasudil were added into inhibitor-treated groups cell culture on the7thday, and incubated for24h. TH immunofluorescence staining was used toobserve axons length and axons number of TH-ir cells.Based on the results of thisexperiment, we chose suitable inhibitor and its final concentrations which hadobvious effects to analyse polymerization β-Tubulin Ⅲexpression in cell extractsof dehydranter(described above) treated control and inhibitor-treated groups.Results①Axon length of control groups was(88.45±17.12)μm, and that of5、10、20、30μM LiCl-treated was (119.03±25.19),(115.92±20.10),(97.21±15.58),(88.31±16.26) μm。 Comparing to the control groups,there were statisticalsignificance at5and10μM LiCl-treated groups,but were not at20and30μMLiCl-treated groups. Axons number of control groups was (1.56±0.32), and of5,10,20,30μM LiCl-treated groups was (1.75±0.41),(1.66±0.33),(1.65±0.3),(1.64±0.38). Comparing to the control groups, there were no statisticalsignificance at various LiCl-treated groups.②A xons length of controlgroups was(88.45±17.12)μm, and of25,50,100,150μM Fasudil-treated groups was(95.97±20.67),(118.30±19.11),(132.39±26.95),(87.01±25.89)μm. Comparing tocontrol groups,there were statistical significance at50and100μM Fasudil-treatedgroups,but were no at25and150μM Fasudil-treated groups. Axons number ofcontrol groups was (1.55±0.29), and of25,50,100,150μM Fasudil-treated groupswas (1.69±0.43),(1.65±0.35),(1.53±0.38),(1.57±0.50). Comparing to controlgroups, there were no statistical significance at various Fasudil-treated groups.③Western-blot analysis showed mean density ratio of β-TubulinⅢ in cellextracts in5μM,10μM LiCl-treated groups was5.68±0.29and5.35±0.22, controlgroups was3.56±0.14. Comparing to control groups,there were statisticalsignificance at5and10μM LiCl-treated groups,but were no at20and30μMLiCl-treated groups. β-Tubulin Ⅲ expression in cell extracts inceasedat5μM and10μM LiCl-treated.④Western-blot analysis showed mean density ratio ofβ-Tubulin Ⅲ in cell extracts in50,100μM Fasudil-treated groups was4.61±0.32and4.45±0.21, control groups was2.76±0.16. Comparing to control groups,therewere statistical significance at50and100μM Fasudil-treated groups,but were noat25and150μM Fasudil-treated groups. β-Tubulin Ⅲexpression in cell extractsinceased at50μM and100μM Fasudil-treated. Conclusion PI3-kinase/Akt/GSK-3β and Rho/ROCK signal pathways associated with dopaminergic axonaldegeneration in PD.Suitable concentrations of LiCl and Fasudil could protectdegenerate dopaminergic axon by its inhibitory effects on signal pathway.
第一部分：一个新的帕金森病多巴胺能神经元轴突变性体外实验细胞模型的建立
目的：利用1-甲基-4-苯基吡啶离子(MPP~+)对小鼠胚胎中脑多巴胺能神经元的毒性作用，建立一个新的PD多巴胺能神经元轴突变性体外实验细胞模型。方法：采用C57BL/6小鼠胚胎(孕14d)中脑腹侧组织进行原代细胞培养，实验分为对照组和不同浓度(0.1、0.5、1.0、10.0μM) MPP~+药物实验组，应用酪氨酸羟化酶(TH)免疫荧光化学细胞染色方法对DAG神经元损伤的形态学进行观察，对DAG神经元数量、轴突数目和长度分别在2、4、6、8、12、24h共6个时间点进行研究。TUNEL检测细胞凋亡情况。结果：MPP~+作用于DAG神经元后细胞数量减少，绝大多数表现为胞体存在，轴突的数目及长度明显减少，网状交织的轴突变得稀疏，表面不光滑，有的呈串珠样肿胀或轴突中断，少数表现为胞体空虚、丢失，仅有轴突存在。DAG神经元细胞数量、轴突长度、轴突数目的减少，对MPP~+有时间-剂量依赖性。分析数据发现只有10.0μM MPP~+作用DAG神经元24小时组在神经元数量、轴突长度、轴突数目这三个方面与其余各组之间比较有显著性差异(P<0.05)。此时，对照组DAG神经元的数量、轴突长度、轴突数目分别为(254±11)个/孔、(158.99±12.13)μm/个、(1.82±0.30)个，MPP~+实验组为(126±16)个/孔、(64.18±19.06) μm/个、(1.17±0.35)个。DAG神经元数量减少了50.39%，每个DAG神经元轴突长度减少了59.8%，每个DAG神经元的轴突数目减少35.7%。TUNEL检测10.0μM MPP~+作用DAG神经元24小时后DAG神经元以凋亡为主，占丢失细胞总数的90.7%。结论:0.1、0.5、1.0、10.0μM MPP~+均能引起DAG神经元损伤，形态改变、数量减少、轴突长度变短、数目减少。而以10.0μM MPP~+作用多巴胺能神经元24小时造模最为理想。
第二部分:帕金森病多巴胺能神经元轴突变性指标的检测
目的：观察淀粉样前体蛋白(APP)和微管蛋白β-TubulinⅢ在MPP~+作用DAG神经元后表达的变化情况，从轴浆运输障碍、微管出现解聚两方面来验证MPP~+诱导的DAG神经元轴突发生了变性。方法：分MPP~+实验组和对照组。细胞培养7天后，实验组应用10.0μM MPP~+作用24h，对照组不予任何干预。TH-APP免疫荧光双标来检测DAG神经元APP的表达。Weston-blot检测细胞β-TubulinⅢ的表达变化。MPP~+实验组使用含有洗脱剂的4%多聚甲醛固定，洗出游离的微管蛋白，检测细胞聚合状态的微管蛋白。对照组使用4%多聚甲醛固定，检测细胞总的微管蛋白。结果：对照组DAG神经元及轴突形态正常， APP呈低表达。MPP~+作用后DAG神经元轴突出现片段化，APP表达升高，在轴突中可见APP局部浓集。Weston-blot检测细胞β-TubulinⅢ的表达，对照组平均灰度值比值为10.08±0.6，实验组为4.36±0.3，与对照组相比实验组下降了56.75%。结论：10.0μM MPP~+作用DAG神经元24h，出现了轴浆运输障碍及轴突微管解聚现象，轴突发生了变性。
第三部分:帕金森病多巴胺能神经元轴突变性相关信号通路的研究
目的：探讨PI3-kinase/Akt/GSK-3β和Rho/ROCK信号通路可能参与了MPP~+诱导的DAG神经元轴突变性。方法：在已建立的细胞模型中使用GSK-3β抑制剂LiCl和ROCK抑制剂Fasudil。LiCl作用浓度为5、10、20、30μM，Fasudil作用浓度为25、50、100、150μM。研究分对照组和实验组。对照组细胞培养7天后，应用10.0μMMPP~+作用24h。实验组细胞培养7天后，应用10.0μM MPP~++不同浓度LiCl或10.0Μm MPP~++不同浓度Fasudil作用24h。TH免疫荧光染色观察轴突长度、轴突数目；实验组将有抑制作用浓度的LiCl、Fasudil组使用洗脱剂和对照组使用洗脱剂洗去游离的微管蛋白，用Weston-blot检测细胞聚合状态β-TubulinⅢ的表达。结果：①对照组轴突长度为(88.45±17.12)μm，实验组5、10、20、30μM LiCl作用后轴突长度分别为(119.03±25.19)、(115.92±20.10)、(97.21±15.58)、(88.31±16.26)μm。5、10μMLiCl组与对照组相比有显著性差异(P<0.05)，20、30μM LiCl组与对照组相比无显著性差异(P＞0.05)。而5和10μM LiCl组、20和30μM LiCl组间无显著性差异(P＞0.05)。对照组轴突数目为(1.56±0.32)个，实验组5、10、20、30μM LiCl作用后轴突长度分别为(1.75±0.41)、(1.66±0.33)、(1.65±0.30)、(1.64±0.38)个，与对照组相比各浓度LiCl组无显著性差异(P＞0.05)。②对照组轴突长度为(86.34±16.18)μm，实验组25、50、100、150μM Fasudil作用后轴突长度分别为(95.97±20.67)、(118.30±19.11)、(132.39±26.95)、（87.01±25.89）μm。50、100μM Fasudil组与对照组相比有显著性差异(P<0.05)，25、150μMFasudil组与对照组相比无显著性差异(P＞0.05)。而50和100μMFasudil组、25和150μMFasudil组间无显著性差异(P＞0.05)。对照组轴突数目为(1.55±0.29)个，实验组25、50、100、150μM Fasudil作用后轴突数目分别为(1.69±0.43)、(1.65±0.35)、(1.53±0.38)、(1.57±0.50)个，与对照组相比各浓度Fasudil组无显著性差异(P＞0.05)。Weston-blot检测细胞β-TubulinⅢ：③LiCl组实验结果显示：平均灰度值比值5μM LiCl组为5.68±0.29，10μM LiCl组为5.35±0.22，对照组为3.56±0.14，实验组与对照组有显著性差异(p＜0.05)，实验组之间无显著性差异（P＞0.05）。5、10μM LiCl作用后聚合状态β-TubulinⅢ的表达增高，其抑制了变性DAG轴突微管蛋白的解聚。④Fasudil组实验结果显示：平均灰度值比值50μM Fasudil组为4.61±0.32，100μMFasudil组为4.45±0.21，对照组为2.76±0.16，实验组与对照组有显著性差异(p＜0.05)，实验组之间无显著性差异(P＞0.05)。50、100μM Fasudil作用后聚合状态β-TubulinⅢ的表达增高，其抑制了变性DAG轴突微管蛋白的解聚。结论：PI3-kinase/Akt/GSK-3β和Rho/ROCK信号通路参与了MPP~+诱导的DAG神经元轴突变性。 LiCl、Fasudil在合适的浓度可以发挥信号通路抑制作用而保护了变性的DAG神经元轴突。
Parkinson’s disease(PD) is a common progressive and neurodegenerativedisease in central nervous system.The primary pathology of PD is selective lossof dopaminergic neurons in the substantia nigra pars compacta.Previous studiesmainly focused on the mechanisms of dopaminergic neurona apoptosis.Axonaldegeneration of dopaminergic neurons was thought to be accompanied withneurons’ loss for a long time.Recently,some findings have demonstrated thatsimply inhibiting process of dopaminergic neurons apotosis could not postponethe onset and development of PD efficiently. Dopaminergic axonal degenerationmight be a key feature and target for PD.Although we have been graduallyconvinced of the important role of axonal degeneration in PD, the mechanismsand the role of axonal degeneration remain unknown. And,we have little specialmethods to treat the axonal degeneration in PD.So the studying of mechanismsand the role of axonal degeneration in PD will not only bring us new theories,butalso bring us new strategies and target to treat PD.
Part1. Establishment of a new cell model of dopaminergic axonal degeneration for Parkinson’s disease in vitro
Objective To investigate dopaminergic axonal degeneration induced by MPP~+in mouse ventral mesencephalic culture and establish a new cell model for PDresearch in vitro. Methods C57BL/6mouse embroys of14d were used to makeventral mesencephalic dissociated culture. And it was divided into the control andMPP~+-treated groups. Different final concentrations (0.1,0.5,1.0and10.0μM) ofMPP~+were added into the MPP~+-treated groups on the7th day and then incubated.By application of anti-tyrosine hydroxylase (TH) monoclone antibodyimmunostaining, we observed morphology,axons length,axons number andamount of dopaminergic neurons at the time of2,4,6,8,12,24h. TUNEL was usedto identify the apoptotic dopaminergic neurons. Results Followed by MPP~+induced injury, TH-ir cells decreased and morphology changed obviously.Although most cell bodies existed, axons length and number decreased. Cellularinterlaced axons were sparse and unsmooth with a string of beads swelling orsegments. A few of TH-ir cells showed axon existed but cell body loss. Thesephenomena including TH-ir cells,axons length and number decreased,which weredependent on dose and time of MPP~+-treated. We found that decrease of cellamounts,axons length and number by10.0μM MPP~+for24h had statisticalsignificance. At this time, TH-ir cells, axons length and number was (254±11)/perwell,(158.99±12.13)μm/per cell,(1.82±0.30)/per cell in control groups,and(126±16)/per well,(64.18±19.06) μm/per cell,(1.17±0.35)/per cell in MPP~+-treated groups. TH-ir cells, axons length and number had decreased50.39%,59.8%,59.8%. Amount of apototic TH-ir cell accounted for90.7%in all losscells,which indicated that apotosis was the main mode of cells loss in thisexperiment system. Conclusion MPP~+with different final concentrations(0.1,0.5,1.0and10.0μM) could cause injury related morphological changs to TH-ir cells,axon length and number.It was the best method that10.0μM MPP~+treated dopaminergic neurons for24h for the model.
Part2. Identified dopaminergic axonal degeneration in Parkinson’s disease
Objective To study axon degeneration of MPP~+-treated dopaminergic neurons inPD by detecting amyloid precursor protein (APP)and microtube proteinβ-Tubulin Ⅲ to observe the fact ofaxonal transport defect and microtubedisassembled. Methods It was divided into control and MPP~+-treated groups.MPP~+with final concentration(10.0μM) were added into the MPP~+-treated groupson the7th day,and incubated for24h.Control groups were treated by nothing.Double staining with TH and APP immunofluorescence detected the expressionof APP in dopaminergic neurons. To detect the expression of β-TubulinⅢ in cellextracts, MPP~+-treated groups were fixed with4%paraformaldehyde whichcontained dehydranter (0.1M PB,10mM EGTA,2mM MgCl2,0.2%Triton X-100)to remove dissociative and left polymerization microtube protein.Controlgroups were fixed with4%paraformaldehyde only. Results TH-ir cells withlow expression of APP were normal in control groups. TH-ir axons with highexpression of APP,and APP local accumulation were segments in MPP~+-treatedgroups. Western-blot analysis showed polymerization microtube proteinβ-TubulinⅢ in cell extracts that mean density ratio of MPP~+-treated groups was4.36±0.3,and control groups was10.08±0.6, β-Tubulin Ⅲ expressionin cellextracts of MPP~+-treated groups was decreased56.75%than controlgroups.Conclusion10.0μM MPP~+treated for24h caused dopamineric axondegeneraton, axonal transport defect and microtube disassembled.
Part3. Exploring dopaminergic axonal degeneration associated signalpathways in Parkinson’s disease
Objective To explore dopaminergic axonal degeneration associated signal pathways in PD.Methods Final concentrations of GSK-3β inhibitor lithiumchloride(5、10、20、30μM) and ROCK inhibitor Fasudil (25、50、100、150μM)wereadministrated to the cell model that we had established. It was divided intocontrol and inhibitor-treated groups.10.0μMMPP~+treated the control groups onthe7th day,and incubated for24h.10.0μΜMPP~+and various final concentrationsLiCl or Fasudil were added into inhibitor-treated groups cell culture on the7thday, and incubated for24h. TH immunofluorescence staining was used toobserve axons length and axons number of TH-ir cells.Based on the results of thisexperiment, we chose suitable inhibitor and its final concentrations which hadobvious effects to analyse polymerization β-Tubulin Ⅲexpression in cell extractsof dehydranter(described above) treated control and inhibitor-treated groups.Results①Axon length of control groups was(88.45±17.12)μm, and that of5、10、20、30μM LiCl-treated was (119.03±25.19),(115.92±20.10),(97.21±15.58),(88.31±16.26) μm。 Comparing to the control groups,there were statisticalsignificance at5and10μM LiCl-treated groups,but were not at20and30μMLiCl-treated groups. Axons number of control groups was (1.56±0.32), and of5,10,20,30μM LiCl-treated groups was (1.75±0.41),(1.66±0.33),(1.65±0.3),(1.64±0.38). Comparing to the control groups, there were no statisticalsignificance at various LiCl-treated groups.②A xons length of controlgroups was(88.45±17.12)μm, and of25,50,100,150μM Fasudil-treated groups was(95.97±20.67),(118.30±19.11),(132.39±26.95),(87.01±25.89)μm. Comparing tocontrol groups,there were statistical significance at50and100μM Fasudil-treatedgroups,but were no at25and150μM Fasudil-treated groups. Axons number ofcontrol groups was (1.55±0.29), and of25,50,100,150μM Fasudil-treated groupswas (1.69±0.43),(1.65±0.35),(1.53±0.38),(1.57±0.50). Comparing to controlgroups, there were no statistical significance at various Fasudil-treated groups.③Western-blot analysis showed mean density ratio of β-TubulinⅢ in cellextracts in5μM,10μM LiCl-treated groups was5.68±0.29and5.35±0.22, controlgroups was3.56±0.14. Comparing to control groups,there were statisticalsignificance at5and10μM LiCl-treated groups,but were no at20and30μMLiCl-treated groups. β-Tubulin Ⅲ expression in cell extracts inceasedat5μM and10μM LiCl-treated.④Western-blot analysis showed mean density ratio ofβ-Tubulin Ⅲ in cell extracts in50,100μM Fasudil-treated groups was4.61±0.32and4.45±0.21, control groups was2.76±0.16. Comparing to control groups,therewere statistical significance at50and100μM Fasudil-treated groups,but were noat25and150μM Fasudil-treated groups. β-Tubulin Ⅲexpression in cell extractsinceased at50μM and100μM Fasudil-treated. Conclusion PI3-kinase/Akt/GSK-3β and Rho/ROCK signal pathways associated with dopaminergic axonaldegeneration in PD.Suitable concentrations of LiCl and Fasudil could protectdegenerate dopaminergic axon by its inhibitory effects on signal pathway.
引文
1. Parkinson J. An Essay on Shaking Palsy. Sherwood,Neeley and Jones,London,1817
2. De Rijk MC, Breteler MM, Graveland GA, Ott A, Grobbee DE, van derMeche FG, Hofman A. Prevalence of Parkinson's disease in the elderly: theRotterdam Study. Neurology,1995,45(12):2143-2146
3. Tanner CM, Ottman R, Goldman SM, et al.Parkinson disease in twins: anetiologic study. JAMA,1999,281(4):341-346
4. Zhang J, Perry G, Smith MA, Robertson D,Olson SJ,et al. Parkinson’sdisease is associated with oxidative damage to cytoplasmic DNA and RNAin substantia nigra neurons. Am J Pathol,1999,154(5):1423-1429
5. Zigmond MJ.When it comes to communications between neurons,synapsesare over-rated: insights from an animal model of parkinsonism.Prog BrainRes,2000,125:317-326
6. Kieburtz K,Ravina B. Why hasn't neuroprotection worked in Parkinson'sdisease. Nature Clinical Practice Neurology,2007,3(5):240-241
7. Steward O, Zheng B, Tessier-Lavigne M. False resurrections: distinguishingregenerated from spared axons in the injured central nervous system. J CompNeurol,2003,459(1):1-8
8. Saxena S, Caroni P. Mechanisms of axon degeneration: from development todisease. Prog Neurobiol,2007,83(3):174-191
9. Luo L, O'Leary D.D. Axon retraction and degeneration in development anddisease. Annu Rev Neurosci,2005,28:127-156
10. John ED, Benoilt IG, Virginia M-Y, et al. Is the Initial Insult in Parkinson'sDisease and Dementia with Lewy Bodies a Neuritic Dystrophy?PARKINSON'S DISEASE: The Life Cycle of the Dopamine Neuron-AnnNY Acad Sci,2003,991:295-297
11. Conforti L,Adalbert R,Coleman MP. Neuronal death:where does the endbegin. Trends Neurosci,2007,30(4):159-166
12. Sajadi A,Schneider BL,Aebischer P.Wlds-mediated protection of dopam-inergic fibers in an animal model of Parkinson disease. Current biology: CB,2004,14(4):326-330
13.姚庆和,高国栋.肌苷对帕金森病小鼠模型的神经保护作用.第四军医大学学报,2005,26(2):141-144
14. Dauer W,Przedborski S.Parkinson’s disease: mechanisms and models.Neuron,2003,39(6):889-909
15. Samii A,Nutt JG,Ransom BR.Parkinson’s disease.Lancet,2004,363:1783-1793
16. Moore DJ,West AB,Dawson VL,Dawson TM. Molecular pathophysiology ofParkinson’s disease. Annu Rev Neurosci,2005,28:57-87
17. Riess O, Kruger R, Hochstrasser H, Soehn AS, Nuber S, Franck T,BergD.Genetic causes of Parkinson’s disease: extending the pathway. JNeural Transm Suppl,2006,70:181-189
18. Vila M,Przedborski S.Genetic clues to the pathogenesis of Parkinson’sdisease. Nat Med (Suppl.),2004,10: S58-62
19. Bonifati V,Rizzu P, van Baren MJ,Schaap O,Breedveld GJ,KriegerE,DekkerMC, Squitieri F,et al.Mutations in the DJ-1gene associated with autosomalrecessive early-onset parkinsonism.Science,2003,299(5604):256-259
20. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S,Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene causeautosomal recessive juvenile Parkinsonism. Nature,1998,392(6676):605-608
21. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S,Ali Z, Del Turco D,et al. Hereditary early-onset Parkinson’s disease causedby mutations in PINK1. Science,2004,304(5674):1158-1160
22. Farrer MJ.Genetics of Parkinson disease: paradigm shifts and futureprospects.Nat Rev Genet,2006,7(4):306-318
23. Le W,Appel SH. Mutant genes responsible for Parkinson’s disease. CurrOpin Pharmacol,2004,4(1):79-84
24. Kruger R,Kuhn W,Muller T,Woitalla D, Graeber M, K sel S, Przuntek H, etal.Ala30Promutation in the gene encoding alpha-synuclein in Parkinson’sdisease. Nat Genet,1998,18(2):106-108
25. Paisan-Ruiz C,Jain S, Evans EW,Gilks WP,Simón J, van der Brug M, Lópezde Munain A, et al.Cloning of the gene containing mutations that causePARK8-linked Parkinson’s disease. Neuron,2004,44(4):595-600
26. Polymeropoulos MH, Lavedan C,Leroy E,Ide SE, Dehejia A, Dutra A, PikeB, et al.Mutation in the alpha-synuclein gene identified in families withParkinson’s disease. Science,1997,276(5321):2045-2047
27. Singleton AB,Farrer M,Johnson J,Singleton A, Hague S, Kachergus J, et al.Alpha-synuclein locus triplication causes Parkinson’s disease. Science,2003,302(5646):841
28. Zimprich A,Biskup S,Leitner P,Lichtner P,Farrer M,Lincoln S,et al.Mutations in LRRK2cause autosomal-dominant parkinsonism withpleomorphic pathology. Neuron,2004,44(4):601-607
29. Le WD,Xu P,Jankovic J,Jiang H,Appel SH,Smith RG,Vassilatis DK,Mutations in NR4A2associated with familial Parkinson disease. NatGenet,2003,33(1):85-89
30. Leroy E,Boyer R,Auburger G,Leube B, Ulm G, Mezey E,et al. The ubiquitinpathway in Parkinson’s disease. Nature,1998,395(6701):451-452
31. Marx FP, Holzmann C, Strauss KM, Li L, Eberhardt O, Gerhardt E, CooksonMR,et al. Identification and functional characterization of a novel R621Cmutation in the synphilin-1gene in Parkinson’s disease.Hum MolGenet,2003,12(11):1223-1231
32. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D,et al. Loss of function mutations in the gene encoding Omi/HtrA2inParkinson’s disease. Hum Mol Genet.2005,14(15):2099-2111
33. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP,Goebel I,et al. Hereditary parkinsonism with dementia is caused bymutations in ATP13A2, encoding a lysosomal type5P-type ATPase. NatGenet,2006,38(10):1184-1191
34. Gasser T, Muller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, BonifatiV, et al. A susceptibility locus for Parkinson’s disease maps to chromosome2p13. Nat Genet,1998,18(3):262-265
35. Hicks AA,Petursson H,Jonsson T, Stefansson H,Johannsdottir HS,et al. Asusceptibility gene for late-onset idiopathic Parkinson’s disease. AnnNeurol,2002,52(5):549-555
36. Pankratz N, Nichols WC, Uniacke SK,Halter C,Murrell J,Rudolph A, et al.Genome-wide linkage analysis and evidence of gene-by-gene interactions ina sample of362multiplex Parkinson disease families. Hum MolGenet,2003,12(20):2599-2608
37. Pankratz N, Nichols WC, Uniacke SK, Halter C,Rudolph A,et al. Significantlinkage of Parkinson disease to chromosome2q36-37. Am J HumGenet2003,72(4):1053-1057
38. Farrer MJ.Genetics of Parkinson disease: paradigm shifts and futureprospects.Nat Rev Genet,2006,7:306-318
39. Farrer M, Maraganore DM, Lockhart P, Singleton A,Lesnick TG,de AndradeM,et al. Alpha-synuclein gene haplotypes are associated with Parkinson’sdisease. Hum Mol Genet,2001,10(17):1847-1851
40. Kruger R,Vieira-Saecker AM, Kuhn W, Berg D,Muhnl N,Fuchs GA,et al.Increased susceptibility to sporadic Parkinson’s disease by a certaincombined alpha-synuclein/apolipoprotein E genotype. Ann Neurol,1999,45(5):611-617
41. Maraganore DM, Farrer MJ, Hardy JA, Lincoin SJ,et al. Case-control studyof the ubiquitin carboxy-terminal hydrolase L1gene in Parkinson’s disease.Neurology,1999,53(8):1858-1860
42. Satoh J, Kuroda Y.A polymorphic variation of serine to tyrosine at codon18in the ubiquitin C-terminal hydrolase-L1gene is associated with a reducedrisk of sporadic Parkinson’s disease in a Japanese population. J Neurol Sci,2001,189(1-2):113-117
43. Davis GC, Williams AC, Markey SP,Ebert MH,Caine ED,et al. ChronicParkinsonism secondary to intravenous injection of meperidine analogues.Psychiatry Res,1979,1(3):249-254
44. Langston JW,Ballard Jr PA.Parkinson’s disease in a chemist working with1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.N Engl J Med,1983,309(5):310
45. Davis GC, Williams AC, Markey SP, Ebert MH,Caine ED,et al. ChronicParkinsonism secondary to intravenous injection of meperidine analogues.Psychiatry Res,1979,1(3):249-254
46. Burns RS, Chiueh CC, Markey SP, Ebert MH,Jacobowitz DM,Kopin IJ.Aprimate model of parkinsonism: selective destruction of dopaminergicneurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA,1983,80(14):4546-4550
47. Johansson B, Roos BE.5-Hydroxyindoleacetic and homovanillic acid levelsin the cerebrospinal fluid of healthy volunteers and patients with Parkinson’ssyndrome. Life Sci,1967,6:1449-1454
48. Olsson R, Roos BE. Concentrations of5-hydroxyindoleacetic acid andhomovanillic acid in the cerebrospinal fluid after treatment with probenecidin patients with Parkinson’s disease. Nature,1968,219:502-503
49. Heikkila RE,Manzino L,Cabbat FS,Duvoisin RC. Protection against thedopaminergic neurotoxicity of1-methyl-4-phenyl-1,2,5,6-tetrahydropyridineby monoamine oxidase inhibitors. Nature,1984,311(5985):467-469
50. Langston JW, Irwin I, Langston EB, Forno LS. Pargyline prevents MPTPinduced parkinsonism in primates. Science,1984,225(4669):1480-1482
51. Markey SP,Johannessen JN,Chiueh CC,Burns RS,Herkenham MA.Intraneuronal generation of a pyridinium metabolite may cause drug-inducedparkinsonism. Nature,1984,311(5985):464-467
52. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH.Parkinsonisminducingneurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of themetabolite N-methyl-4-phenylpyridine by dopamine neurons explainsselective toxicity. Proc Natl Acad Sci USA,1985,82(7):2173-2177
53. Chiba K, Trevor A, Castagnoli N Jr. Metabolism of the neurotoxic tertiaryamine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun,1984,120(2):574-578
54. Heikkila RE, Nicklas WJ, Duvoisin RC. Dopaminergic toxicity after thestereotaxic administration of the1-methyl-4-phenylpyridinium ion (MPP+)to rats. Neurosci Lett,1985,59(1):135-140
55. Nicklas WJ,Vyas I,Heikkila RE.Inhibition of NADH-linked oxidation inbrain mitochondria by1-methyl-4-phenyl-pyridine,a metabolite of theneurotoxin,1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.Life Sci,1985,36(26):2503-2508
56. Bindoff LA,Birch-Machin M,Cartlidge NE, Parker WD Jr,TurnbullDMMitochondrial function in Parkinson’s disease. Lancet,1989,2(8653):49
57. Bindoff LA, Birch-Machin M, Cartlidge NE, Parker WD Jr,Turnbull DM.Respiratory chain abnormalities in skeletal muscle from patients withParkinson’s disease. J Neurol Sci,1991,104(2):203-208
58. Parker Jr WD, Boyson SJ, Parks JK. Abnormalities of the electron transportchain in idiopathic Parkinson’s disease. Ann Neurol,1989,26:719-723
59. Schapira AH,Cooper JM,Dexter D,Clark JB,Jenner P,Marsden CD.Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem,1990,54(3):823-827
60. Hartley A,Stone JM,Heron C,Cooper JM,Schapira AH. Complex I inhibitorsinduce dose-dependent apoptosis in PC12cells: relevance to Parkinson’sdisease. J Neurochem,1994,63(5):1987-1990
61. McNaught KS, Thull U, Carrupt PA, Altomare C,Cellamare S,Carotti A,et al.Inhibition of complex I by isoquinoline derivatives structurally related to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem Pharmacol,1995,50(11):1903-1911
62. McNaught KS, Thull U, Carrupt PA, Altomare C, Cellamare S, Carotti A,Testa B, et al. Effects of isoquinoline derivatives structurally related to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrialrespiration. Biochem Pharmacol,1996,51(11):1503-1511
63. McNaught KS,Thull U,Carrupt PA, Altomare C, Cellamare S, Carotti A,Testa B, Jenner P, Marsden CD.Toxicity to PC12cells of isoquinolinederivatives structurally related to1-methyl-4-phenyl-1,2,3,6-tetrahydropy-ridine. Neurosci Lett,1996,206(1):37-40
64. Seaton TA,Cooper JM,Schapira AH.Free radical scavengers protect do-paminergic cell lines from apoptosis induced by complex I inhibitors. BrainRes,1997,777(1-2):110-118
65. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV, GreenamyreJT.Chronic systemic pesticide exposure reproduces features of Parkinson’sdisease. Nat Neurosci,2000,3(12):1301-1306
66. McNaught KS, Thull U, Carrupt PA, Altomare C,Cellamare S,Carotti A,et al.Nigral cell loss produced by infusion of isoquinoline derivatives structurallyrelated to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration,1996,5(3):265-274
67. Yoshida M,Niwa T,Nagatsu T.Parkinsonism in monkeys produced bychronic administration of an endogenous substance of the brain, tetrahydro-isoquinoline: the behavioral and biochemical changes. Neurosci Lett,1990,119(1):109-113
68. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV,Greenamyre JT.Chronic systemic pesticide exposure reproduces features ofParkinson’s disease. Nat Neurosci,2000,3(12):1301-1306
69. Ferrante RJ, Schulz JB, Kowall NW, Beal MF.Systemic administration ofrotenone produces selective damage in the striatum and globus pallidus, butnot in the substantia nigra. Brain Res,1997,753(1):157-162
70. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV, GreenamyrJT.Chronic systemic pesticide exposure reproduces features of Parkinson’sdisease. Nat Neurosci,2000,3(12):1301-1306
71. Lai BC,Marion SA,Teschke K, Tsui JK. Occupational and environmentalrisk factors for Parkinson’s disease. Parkinsonism Relat. Disord,2002,8:297-309
72. Young AB, Penney JB. Biochemical and functional organization of the basalganglia, in: J. Jankovic, E. Tolosa (Eds.), Parkinson’s Disease and MovementDisorders, Williams and Wilkins, Baltimore,1993, pp.1-11
73. German DC,Manaye K,Smith WK,Woodward DJ,Saper CB.Midbraindopaminergic cell loss in Parkinson’s disease: computer visualization. AnnNeurol,1989,26(4):507-514
74. Ma Y, Dhawan V, Mentis M, Chaly T, Spetsieris PG,Eidelberg D.Parametric mapping of [18F]FPCIT binding in early stage Parkinson’sdisease: a PET study.Synapse,2002,45(2):125-133
75. Damier P,Hirsch EC,Agid Y,Graybiel AM. The substantia nigra of thehuman brain:II Patterns of loss of dopamine-containing neurons inParkinson’s disease. Brain,1999,122(pt8):1437-1448
76. Nurmi E,Ruottinen HM,Bergman J,Haaparanta M,Solin O,et al.Rate ofprogression in Parkinson’s disease:a6-[18F]fluoro-l-dopa PET study.MovDisord,2001,16(4):608-615
77. Di Monte DA.The environment and Parkinson’s disease:is the nigrostriatalsystem preferentially targeted by neurotoxins?.Lancet Neurol,2003,2(9):531-538
78. Steece-Collier K,Maries E,Kordower JH.Etiology of Parkinson’s disease:genetics and environment revisited, Proc Natl Acad Sci USA,2002,99(22):13972-13974
79. Payami H,Zareparsi S.Genetic epidemiology of Parkinson’s disease.J GeriatrPsychiatry Neurol,1998,11(2):98-106
80. Burke RE.Recent advances in research on Parkinson disease:synuclein andparkin.Neurologist,2004,10(2):75-81
81. Hu CJ,Sung SM,Liu H,Chang JG.No mutation of G209A in the alpha-synuclein gene in sporadic Parkinson’s disease among Taiwan Chinese.EurNeurol,1999,41(2):85-87
82. Scott WK, Yamaoka LH, Stajich JM, et al.The alphasynuclein gene is not amajor risk factor in familial Parkinson disease.Neurogenetics,1999,2:191-192
83. Brecknell JE, Dunnett SB, Fawcett JW. A quantitative study of cell death inthe substantia nigra following a mechanical lesion of the medial forebrainbundle. Neuroscience,1995,64(1):219-227
84. Faull RL, Mehler WR.The cells of origin of nigrotectal,nigrothalamic andnigrostriatal projections in the rat. Neuroscience,1978,3(11):989-1002
85. Deumens R, Blokland A, Prickaerts J. Modeling Parkinson’s disease in rats:an evaluation of6-OHDA lesions of the nigrostriatal pathway. Exp Neurol,2002,175(2):303-317
86. Hirsch EC,Hoglinger G,Rousselet E, Breidert T,Parain K,et al.Animalmodels of Parkinson’s disease in rodents induced by toxins:an update.JNeural Transm Suppl,2003,(65):89-100
87. Olney JW,Zorumski CF,Stewart GR,Price MT,Wang GJ,Labruyere J.Excitotoxicity of L-dopa and6-OH-dopa:implications for Parkinson’s andHuntington’s diseases. Exp Neurol,1990,108(3):269-272
88. Burns RS,LeWitt PA,Ebert MH,Pakkenberg H,Kopin IJ.The clinicalsyndrome of striatal dopamine deficiency; parkinsonism induced by MPTP.N Engl J Med,1985,312(22):1418-1421
89. Langston JW.The case of the tainted heroin. Sciences,1985,25:34-40
90. Langston JW, Palfreman J. The Case of the Frozen Addicts.Vintage Books,New York,1996
91. Jenner P.The contribution of the MPTP-treated primate model to thedevelopment of new treatment strategies for Parkinson’s disease.Parkinsonism Relat Disord,2003,9(3):131-137
92. Kopin IJ, Markey SP.MPTP toxicity:implications for research in Parkinson’sdisease, Annu Rev Neurosci,1988,11:81-96
93. Wichmann T,DeLong MR.Pathophysiology of Parkinson’s disease:theMPTP primate model of the human disorder.Ann N Y Acad Sci,2003,991:199-213
94. Hamre K,Tharp R,Poon K,Xiong X,Smeyne RJ.Differential strain suscepti-bility following1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) admi-nistration acts in an autosomal dominant fashion: quantitative analysis inseven strains of Mus musculus.Brain Res.1999,828(1-2):91-103
95. Mitra N,Mohanakumar KP,Ganguly DK.Resistance of golden hamster to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: relation-ship with low levelsof regional monoamine oxidase B.J Neurochem,1994,62:1906-1912
96. Riachi NJ,Harik SI. Strain differences in systemic1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in mice correlate best with monoamineoxidase activity at the blood-brain barrier.Life Sci,1988,42:2359-2363
97. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV,Greenamyre JT.Chronic systemic pesticide exposure reproduces features ofParkinson’s disease.Nat Neurosci,2000,3(12):1301-1306
98. Brooks AI,Chadwick CA,Gelbard HA,Cory-Slechta DA,Federoff HJ.Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuronloss. Brain Res,1999,823(1-2):1-10
99. Chun HS,Gibson GE,DeGiorgio LA, Zhang H,Kidd VJ,SonJH.Dopaminergic cell death induced by MPP(+), oxidant and specificneurotoxicants shares the common molecular mechanism. J Neurochem,2001,76(4):1010-1021
100. Thiruchelvam M,Richfield EK,Baggs RB,Tank AW,Cory-Slechta DA..Thenigrostriatal dopaminergic system as a preferential target of repeatedexposures to combined paraquat and maneb:implications for Parkinson’sdisease.J Neurosci,2000,20(24):9207-9214
101.Kalaria RN, Mitchell MJ, Harik SI. Correlation of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood–brain barrier monoamineoxidase activity. Proc Natl Acad Sci U S A,1987,84:3521-3525
102.Riachi NJ, Harik SI, Kalaria RN, Savre LM. On the mechanisms underlying1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: II Susceptibilityamong mammalian species correlates with the toxin’s metabolic patterns inbrain microvessels and liver, JPET,1988,244(2)443-448
103.Riachi NJ,Dietrich WD,Harik SI. Effects of internal carotid administration ofMPTP on rat brain and blood-brain barrier, Brain Res,1990,533(1):6-14
104.Brooks WJ,Jarvis MF,Wagner GC. Astrocytes as a primary locus for theconversion MPTP into MPP+. J Neural Transm,1989,76(1):1-12
105.Hazell AS,Itzhak Y,Liu H,Norenberg MD.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreases glutamate uptake in culturedastrocytes. J Neurochem,1997,68(5):2216-2219
106.Kopin IJ.Features of the dopaminergic neurotoxin MPTP. Ann NY AcadSci,1992,648:96-104
107.Marini AM,Lipsky RH,Schwartz JP,Kopin IJ.Accumulation of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in cultured cerebellar astrocytes.JNeurochem,1992,58(4):1250-1258
108.Teismann P,Tieu K,Cohen O,Choi DK,Wu DC,Marks D,et al.Pathogenicrole of glial cells in Parkinson’s disease.Mov Disord,2003,18(2):121-129
109.Ofori S,Schorderet M.Effects of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopamine synthesis and release in the rabbit retina in vitro.Neuropharmacology,1987,26:1607-1610
110.Hunot S,Dugas N,Faucheux B,Hartmann A,Tardieu M,Debre P,et al.FcepsilonRII/CD23is expressed in Parkinson’s disease and induces, in vitro,production of nitric oxide and tumor necrosis factor-alpha in glial cells. JNeurosci,1999,19(9):3440-3447
111.Muramatsu Y,Kurosaki R,Watanabe H,Michimata M,Matsubara M,ImaiY,Araki T.Cerebral alterations in a MPTP-mouse model of Parkinson’sdisease-an immunocytochemical study.J Neural Transm,2003,110(10):1129-1144
112.Przedborski S,Jackson-Lewis V,Yokoyama R,Shibata T,Dawson VL,Dawson TM. Role of neuronal nitric oxide in1-methyl-4-phenyl-1,2,3,6-tetrahy dropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc NatlAcad Sci U SA,1996,93(10):4565-4571
113.Knott C,Stern G,Wilkin GP. Inflammatory regulators in Parkinson’s disease:iNOS,lipocortin-1and cyclooxygenases-1and-2.Mol Cell Neurosci,2000,16:724-739
114.Liberatore GT,Jackson-Lewis V,Vukosavic S,Mandir AS,Vila M,etal.Inducible nitric oxide synthase stimulates dopaminergic neurodegenerationin the MPTP model of Parkinson disease. Nat Med,1999,5(12):1403-1409
115.Wu DC,Jackson-Lewis V,Vila M,Tieu K,Teismann P,Vadseth C,et al.Blockade of microglial activation is neuroprotective in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. JNeurosci,2002,22(5):1763-1771
116.Kitayama S,Wang JB,Uhl GR.Dopamine transporter mutants selectivelyenhance MPP+transport.Synapse,1993,15:58-62
117.Smeyne M, Goloubeva O, Smeyne R.J.Strain-dependent susceptibility toMPTP and MPP+-induced Parkinsonism is determined by glia. Glia,2001,74:73-80
118.Di Monte DA,Wu EY,Irwin I,Delanney LE,Langston JW.Production anddisposition of1-methyl-4-phenylpyridinium in primary cultures of mouseastrocytes. Glia,1992,5(1):48-55
119.Di Monte DA, Royland JE, Irwin I, Langston JW.Astrocytes as the site forbioactivation of neurotoxins. Neurotoxicology,1996,17(3-4):697-703
120.McGeer PL, McGeer EG.Glial cell reactions in neurodegenerative diseases:pathophysiology and therapeutic interventions, Alzheimer Dis AssocDisord,1998,12(Suppl.2):S1-S6
121.McNaught, KSP, Jenner P. Altered glial function causes neuronal death andncreases neuronal susceptibility to1-methyl-4-phenylpyridinium-and6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalicco-cultures.J Neurochem,1999,73:2469-2476
122.Kienzl E,Jellinger K,Stachelberger H,Linert W.Iron as catalyst for oxidativestress in the pathogenesis of Parkinson’s disease? Lif Sci,1999,65:1973-1976
123.Schipper HM, Liberman A,Stopa EG.Neural heme oxygenase-1expressionin idiopathic Parkinson’s disease. Exp Neurol,1998,150:60-68
124.Fernandez-Gonzales A,Perez-Otano I,Morgan JI. MPTP selectively inducesheme oxygenase-1expression in striatal astrocytes.Eur J Neurosci,2000,12:1573-1583
125.Poss KD,Tonegawa S.Heme oxygenase1is required for mammalian ironreutilization. Proc Natl Acad Sci U S A,1997,94:10919-10924
126.Maines MD. The heme oxygenase system: a regulator of second messengergases. Annu Rev Pharmacol Toxicol,1997,37:517-554
127.Dringen R, Pfeiffer B, Hamprecht B.Synthesis of the antioxidant glutathionein neurons: supply by astrocytes of CysGly as precursor for neuronalglutathione.J Neurosci,1999,19:562-569
128.Hatakeyama S,Hayasaki Y,Masuda M, Kazusaka A,Fujita S.Mechanism formouse strain differences in the protective effect of sudan III against the invivo genotoxicity of7,12-dimethylbenz[a]anthracene.Toxicol Lett,1996,89(3):231-239
129.Schaar DG,Sieber BA,Dreyfus CF,Black IB. Regional and cell-specificexpression of GDNF in rat brain. Exp Neurol,1993,124(2):368-371
130.Schaar DG,Sieber BA,Sherwood AC,Dean D,Mendoza G,et al.Multipleastrocyte transcripts encode nigral trophic factors in rat and human.ExpNeurol,1994,130(2):387-393
131.Gong L,Wyatt RJ,Baker I,Masserano JM.Brain-derived and glial cellline-derived neurotrophic factors protect a catecholaminergic cell line fromdopamine-induced cell death.Neurosci Let,1999,263:153-156
132.Kirschner PB, Jenkins BG, Schulz JB,Frnkelstein SP,Matthews RT,et al.NGF, BDNF and NT-5, but not NT-3protect against MPP+toxicity andoxidative stress in neonatal animals. Brain Res,1996,713(1-2):178-185
133.Petersen AA,Larsen KE,Behr GG,Romero N, Przedborski S, BrundinP,Sulzer D..Brain-derived neurotrophic factor inhibits apoptosis anddopamine-induced free radical production in striatal neurons but does notprevent cell death. Brain Res Bull,2001,56(3-4):331-335
134.Heaton MB, Paiva M, Madorsky I, Mayer J,Moore DB.Effects of ethanol onneurotrophic factors, apoptosis-related proteins,endogenous antioxidants, andreactive oxygen species in neonatal striatum: relationship to periods ofvulnerability. Brain Res Dev Brain Res,2003,140(2):237-252
135.Schabitz WR,Sommer C,Zoder W,Kiessling M,Schwaninger M,SchwabS.Intravenous brain-derived neurotrophic factor reduces infarct size andcounterregulates bax and bcl-2expression after temporary focal cerebralischemia. Stroke,2000,31(9):2212-2217
136.Lander ES,Schork NJ.Genetic dissection of complex traits.Science.1994,265:2037-2048[published erratum appears in Science1994Oct21;266(5184):353]
137.Del Zompo M,Piccardi MP,Ruiu S,Quartu M,Gessa GL,Vaccari A.SelectiveMPP+uptake into synaptic dopamine vesicles:possible involvement in MPTPneurotoxicity.Br J Pharmacol,1993,109(2):411-414
138.Ramsay RR,Singer TP.Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria.J Biol Chem,1986,261:7585-7587
139.Ramsay RR,Dadgar J,Trevor A,Singer TP.Energy-driven uptake of N-methyl-4-phenylpyridine by brain mitochondria mediates the neuro-toxicity ofMPTP. Life Sci,1986,39(7):581-588
140.Mizuno Y, Sone N, Suzuki K, Saitoh T. Studies on the toxicity of1-methyl-4-phenylpyridinium ion (MPP+) against mitochondria of mouse brain.JNeurol Sci,1988,86:97-110
141.Beal MF.Mitochondria, oxidative damage, and inflammation in Parkinson’sdisease. Ann NY Acad Sci,2003,991:120-131
142.Muller T,Buttner T,Gholipour AF,Kuhn W.Coenzyme Q10supple-mentation provides mild symptomatic benefit in patients with Parkinson’sdisease. Neurosci Lett,2003,341(3):201-204
143.Cleeter MW,Cooper JM,Schapira AH.Irreversible inhibition of mitochon-drial complex I by1-methyl-4-phenylpyridinium: evidence for free radicalinvolvement. J Neurochem,1992,58:786-789
144.Przedborski S,Kostic V,Jackson-Lewis V,Naini AB,Simonetti S,et al.Transgenic mice with increased Cu/Zn–superoxide dismutase activity areresistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuro-toxicity. J Neurosci,1992,12(5):1658-1667
145.Wu DC,Teismann P,Tieu K,Vila M,Jackson-Lewis V,et al.NADPH oxidasemediates oxidative stress in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease.Proc Natl Acad Sci U S A,2003,100(10):6145-6150
146.Radi R,Cassina A,Hodara R,Quijano C,Castro L.Peroxynitrite reactions andformation in mitochondria.Free Radic Biol Med,2002,33:1451-1464
147.Hamre K,Tharp R,Poon K,Xiong X,Smeyne RJ.Differential strainsusceptibility following1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)administration acts in an autosomal dominant fashion:quantitative analysis inseven strains of Mus musculus.Brain Res,1999,828(1-2):91-103
148.Kuhn DM,Aretha CW,Geddes TJ.Peroxynitrite inactivation of tyrosinehydroxylase:mediation by sulfhydryl oxidation, not tyrosine nitration.JNeurosci,1999,19:10289-10294
149.Ara J,Przedborski S,Naini AB,Jackson-Lewis V,Trifiletti RR,et al.Inactivation of tyrosine hydroxylase by nitration following exposure toperoxynitrite and1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Proc Natl Acad Sci U S A,1998,95(13):7659-7663
150.Liberatore GT,Jackson-Lewis V,Vukosavic S,Mandir AS,Vila M,etal.Inducible nitric oxide synthase stimulates dopaminergic neurodegen-eration in the MPTP model of Parkinson disease.Nat Med,1999,5(12):1403-1409
151.Slivka A,Cohen G.Hydroxyl radical attack on dopamine.J Biol Chem,1985,260:15466-15472
152.Hirrlinger J, Schulz JB, Dringen R. Effects of dopamine on the glutathionemetabolism of cultured astroglial cells: implications for Parkinson’s disease.J Neurochem,2002,82:458-467
153.LaVoie MJ, Hastings TG.Peroxynitrite-and nitrite-induced oxidation ofdopamine: implications for nitric oxide in dopaminergic cell loss.JNeurochem,1999,73:2546-2554
154.Graham DG.Oxidative pathways for catecholamines in the genesis ofneuromelanin and cytotoxic quinones. Mol Pharmacol,1978,14:633-643
155.Hastings TG.Enzymatic oxidation of dopamine: the role of prostaglandin Hsynthase. J Neurochem,1995,64:919-924
156.O’Banion MK. COX-2and Alzheimer’s disease: potential roles in inflam-mation and neurodegeneration. Expert Opin Investig Drugs,1999,8:1521-1536
157.Teismann P,Tieu K,Choi DK,Wu DC,Naini A,Hunot S, et al. Cyclooxy-genase-2is instrumental in Parkinson’s disease neurodegeneration. Proc NatlAcad Sci U S A,2003,100(9):5473-5478
158.Miller GW,Erickson JD,Perez JT,Penland SN,Mash DC,Rye DB,LeveyAL.Immunochemical analysis of vesicular monoamine transporter (VMAT2)protein in Parkinson’s disease.Exp Neurol,1999,156(1):138-148
159.Gainetdinov RR,Fumagalli F,Wang YM,Jone SR,Levey AL,MillerGW,Caron MG.Increased MPTP neurotoxicity in vesicular monoaminetrans porter2heterozygote knockout mice. J Neurochem,1998,70(5):1973-1978
160.Takahashi N, Miner LL,Sora I,Ujike H,Revay RS,Kostic V, et al.VMAT2knockout mice:heterozygotes display reduced amphetamine-conditionedreward,enhanced amphetamine locomotion,and enhanced MPTPtoxicity.Proc Natl Acad Sci U S A,1997,94(18):9938-9943
161.Liu Y,Peter D,Roghani A,Schuldiner S,Prive GG,Eisenberg D,et al.A cDNAthat suppresses MPP+toxicity encodes a vesicular amine transporter.Cell,1992,70(4):539-551
162.Schluter OM,Fornai F,Alessandri MG,Takamori S,Geppert M,Jahn R,SudhofTC.Role of alpha-synuclein in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.Neuroscience,2003,118(4):985-1002
163.Conway KA, Harper JD, Lansbury PT.Accelerated in vitro fibril formationby a mutant alpha-synuclein linked to early-onset Parkinson disease.Nat Med,1998,4:1318-1320
164.Ischiropoulos H, al-Mehdi AB.Peroxynitrite-mediated oxidative proteinmodifications. FEBS Lett,1995,364:279-282
165.Giasson BI,Duda JE,Murray IV,Chen Q,SouzaJM,Hurtiq HI,IschiropoulosH,et al. Oxidative damage linked to neurodegeneration by selectivealphasynuclein nitration in synucleinopathy lesions.Science,2000,290(5493):985-989
166.Giasson BI,Jakes R,Goedert M,Duda JE,Leiqht S,Trojanowski JQ,Lee VM.Apanel of epitope-specific antibodies detects protein domains distributedthroughout human alpha-synuclein in Lewy bodies of Parkinson’s disease. JNeurosci Res,2000,59(4):528-533
167.Souza JM, Giasson BI, Chen Q,Lee VM, Ischiropoulos H.Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. implicationof nitrative and oxidative stress in the pathogenesis of neurodegenerativesynucleinopathies. J Biol Chem,2000,275(24):18344-18349
168.Przedborski S,Chen Q,Vila M,Giasson BI,Djaldatti R,et al.Oxidativepost-translational modifications of alpha-synuclein in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’sdisease.J Neurochem,2001,76(2):637-640
169.Schmidt CJ, Matsuda LA, Gibb JW. In vitro release of tritiated monoaminesfromrat CNS tissue by the neurotoxic compound1-methylphenyl-tetrahydropyridine.Eur J Pharmacol,1984,103:255-260
170.Schmidt J, Mertz K, Morgan JI. Regulation of heme oxygenase-1expressionby dopamine in cultured C6glioma and primary astrocytes. Mol Brain Res,1999,73:50-59
171.Marek K, Jennings D, Seibyl J.Do dopamine agonists or levodopa modifyParkinson’s disease progression?.Eur J Neurol.2002, Suppl.3:15-22
172.Whone AL,Watts RL,Stoessl AJ,Davis M,Reske S,Nahmias C,et al. Slowerprogression of Parkinson’s disease with ropinirole vs. levodopa: theREAL-PET study. Ann Neurol,2003,54(1):93-101
173.Fornai F,Battaglia G,Gesi M,Giorqi FS,Orzi F,Nicoletti F,Ruqqieris.Time-course and dose-response study on the effects of chronic l-DOPAadministration on striatal dopamine levels and dopamine transporterfollowing MPTP toxicity. Brain Res,2000,887(1):110-117
174.Melamed E,Offen D,Shirvan A,Ziv I.Levodopa-an exotoxin or a therapeuticdrug?. J Neurol,2000,247(Suppl2):II135-II139
175.D’Amato RJ,Lipman ZP,Snyder SH.Selectivity of the parkinsonianneurotoxin MPTP: toxic metabolite MPP+binds to neuromelanin.Science,1986,231:987-989
176.Jellinger KA.The role of iron in neurodegeneration: prospects forpharmacotherapy of Parkinson’s disease.Drugs Aging,1999,14:115-140
177.Luo L,O’Leary DD. Axon retraction and degeneration in developmentanddisease. Annu Rev Neurosci,2005,28:127-156
178.Low LK,Cheng HJ.A little nip and tuck: axon refinement duringdevelopment and axonal injury. Curr Opin Neurobiol,2005,15,549-556
179.Gunawardena S,Goldstein LS.Cargo-carrying motor vehicles on the neuronalhighway:transport pathways and neurodegenerative disease.J Neurobiol,2004,58:258-271
180.Bito H, Furuyashiki T, Ishihara H, Shibasaki Y,Ohashi K,Mizuno K,et al. Acritical role for a Rhoassociated kinase, p160ROCK, in determining axonoutgrowth in mammalian CNS neurons. Neuron,2000,26(2):431-441
181.Kozma R, Sarner S, Ahmed S, Lim L. Rho family GTPases and neuronalgrowth cone remodelling: relationship between increased complexityinduced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoAand lysophosphatidic acid. Mol Cell Biol,1997,17(3):1201-1211
182.Yamada KM,Spooner BS,Wessells NK.Axon growth:roles of microfilamentsand microtubules. Proc Natl Acad Sci USA,1970,66:1206-1212
183.Baas PW, Qiang L. Neuronal microtubules: when the MAP is the roadblock.Trends Cell Biol,2005,15:183-187
184.King ME, Kan HM, Baas PW, Erisir A,Glabe CG,Bloom GS. Tau-dependentmicrotubule disassembly initiated by prefibrillar {beta}-amyloid. J Cell Biol,2006,175(4);541-546.
185.Qiang L,Yu W,Andreadis A,Luo M,Baas PW. Tau protects microtubules inthe axon from severing by katanin. J Neurosci,2006,26(12):3120-3129
186.Yu W,Solowska JM,Qiang L,Karabay A,Baird D,Bass PW.Regulation ofmicrotubule severing by katanin subunits during neuronal development. JNeurosci,2005,25(23):5573-5583
187.Coleman M. Axon degeneration mechanisms: commonality amid diversity.Nat Rev Neurosci,2005,6;889-898
188.Gillingwater TH, Wishart TM, Chen PE, Haley JE,Robertson K,et al. Theneuroprotective WldS gene regulates expression of PTTG1and erythroiddifferentiation regulator1-like gene in mice and human cells. Hum MolGenet,2006,15(4):625-635
189.Finn JT, Weil M, Archer F,Siman R,Srinivasan A,Raff MC. Evidence thatWallerian degeneration and localized axon degeneration induced by localneurotrophin deprivation do not involve caspases. J Neurosci,2000,20(4):1333-1341
190.Conforti L, Fang G, Beirowski B, Wang MS,Sorci L,Asress S,Adalbert R,etal. NAD(+) and axon degeneration revisited: Nmnat1cannot substitute forWld(S) to delay Wallerian degeneration. Cell Death Differ,2007,14(1):116-127
191.Araki T,Sasaki Y,Milbrandt J.Increased nuclear NAD biosynthesis andSIRT1activation prevent axonal degeneration.Science,2004,305:1010-1013
192.DiAntonio A, Haghighi AP, Portman SL,Lee JD,Amaranto AM,GoodmanCS.Ubiquitination-dependent mechanisms regulate synaptic growth andfunction. Nature,2001,412(6845):449-452
193.Zhai Q,Wang J,KimA,et al. Involvement of the ubiquitin-proteasome systemin the early stages of Wallerian degeneration. Neuron,2003;39:217-225.
194.Hoopfer ED, McLaughlin T,Watts RJ, et al. Wlds protection distinguishesaxon degeneration following injury from naturally occurring developmentalpruning. Neuron,2006;50:883-895.
195.KerschensteinerM, Schwab ME, Lichtman JW, Misgeld T. In vivo imagingof axonal degeneration and regeneration in the injured spinal cord.Nat Med,2005;11:572-577.
196.Awasaki T, Tatsumi R, Takahashi K, et al. Essential role of the apoptotic cellengulfment genes draper and ced-6in programmed axon pruning duringDrosophila metamorphosis.Neuron,2006;50;855-867.
197.MacDonald JM, Beach MG, Porpiglia E, Sheehan AE, Watts RJ, FreemanMR. The Drosophila cell corpse engulfment receptor Draper mediates glialclearance of severed axons. Neuron,2006,50(6):869-881
198.Zhou Z,Hartwieg E,Horvitz HR. CED-1is a transmembrane receptor thatmediates cell corpse engulfment in C elegans. Cell,2001,104:43-56
199.MacInnis BL,Campenot RB.Regulation of Wallerian degeneration and nervegrowth factor withdrawal-induced pruning of axons of sympathetic neuronsby the proteasome and the MEK/Erk pathway. Mol Cell Neurosci,2005,28:430-439
200.Beirowski B,Berek L,Adalbert R,Wagner D,Grumme DS,Addicks K,Ribchester RR,Coleman MP.Quantitative and qualitative analysis ofWallerian degeneration using restricted axonal labelling in YFP-H mice.JNeurosci Methods,2004,134(1):23-35
201.Parson SH, Mackintosh CL, Ribchester RR. Elimination of motor nerveterminals in neonatal mice expressing a gene for slow Walleriandegeneration (C57Bl/Wlds). Eur J Neurosci,1997;9:1586-1592
202.Lee T,Marticke S,Sung C,Robinow S, Luo L.Cell-autonomous requirementof the USP/EcR-B ecdysone receptor for mushroom body neuronalremodeling in Drosophila. Neuron,2000,28(3):807-818.
203.Schubiger M,Wade AA,Carney GE,Truman JW,Bennder M.DrosophilaEcR-B ecdysone receptor isoforms are required for larval molting and forneuron remodeling during metamorphosis.Development,1998,125(11):2053-2062
204.Weimann JM, Zhang YA, Levin ME, Devine WP,Brulet P,McConnell SK.Cortical neurons require Otx1for the refinement of exuberant axonalprojections to subcortical targets. Neuron,1999,24(4):819-831
205.Zhang YA,Okada A,Lew CH,McConnell SK. Regulated nuclear traffickingof the homeodomain protein otx1in cortical neurons. Mol CellNeurosci,2002,19(3):430-446
206.Watts RJ,Hoopfer ED,Luo L.Axon pruning during Drosophilametamorphosis: evidence for local degeneration and requirement of theubiquitin-proteasome system. Neuron,2003,38:871-885
207.MacInnis BL,Campenot RB.Regulation of Wallerian degeneration and nervegrowth factor withdrawal-induced pruning of axons of sympathetic neuronsby the proteasome and the MEK/Erk pathway.Mol Cell Neurosci,2005,28:430-439
208.Kuo CT,Zhu S,Younger S,Jan LY,Jan YN.Identification of E2/E3ubiquitinating enzymes and caspase activity regulating Drosophila sensoryneuron dendrite pruning. Neuron,2006,51(3):283-290
209.Williams DW,Kondo S,Krzyzanowska A,Hiromi Y,Truman JWl.Localcaspase activity directs engulfment of dendrites during pruning.NatNeurosci,2006,9(10):1234-1236
210.Watts RJ,Schuldiner O, Perrino J, Larsen C,Luo L. Glia engulf degeneratingaxons during developmental axon pruning. Curr Biol,2004,14(8):678-684
211.Awasaki T,Ito K. Engulfing action of glial cells is required for programmedaxon pruning during Drosophila metamorphosis. Curr Biol,2004,14:668-677
212.Griffin JW,Georges EB,Hsieh ST,Glass JD.Axonal degeneration anddisorders of the axonal cytoskeleton. In:Waxman SG,Jeffery DK,Stys PK(Eds),The Axon: Structure, Function and Pathophysiology.Oxford UniversityPress, New York, pp.375-390
213.Raff MC,Whitmore AV,Finn JT.Axonal self-destruction and neurodegen-eration. Science,2002,296:868-871
214.Gould TW,Buss RR,Vinsant S,Prevette D,Sun W,Knudson CM,et al.Complete dissociation of motor neuron death from motor dysfunction by Baxdeletion in a mouse model of ALS. J Neurosci,2006,26(34):8774-8786
215.Pun S,Santos AF,Saxena S,Xu L,Caroni P. Selective vulnerability andpruning of phasic motoneuron axons in motoneuron disease alleviated byCNTF. Nat Neurosci,2006,9(3):408-419
216.Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neuronsand their nonneuronal neighbors. Neuron,2006,52:39-59
217.Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; amotor neuron-specific disease. Neuron,2005,48:885-896
218.Gurney ME,Pu H,Chiu AY,Dal Canto MC,Polchow CY,Alexander DD,et al.Motor neuron degeneration in mice that express a human Cu,Zn superoxidedismutase mutation. Science,1994,264(5166):1772-1775
219.Wong RO,Meister M,Shatz CJ.Transient period of correlated burstingactivity during development of the mammalian retina. Neuron,1993,11(5):923-938
220.Collard JF,Cote F,Julien JP.Defective axonal transport in a transgenic mousemodel of amyotrophic lateral sclerosis. Nature,1995,375:61-64
221.Boillee S,Vande Velde C,Cleveland DW. ALS: a disease of motor neuronsand their nonneuronal neighbors. Neuron,2006,55:30-40
222.Lino MM,Schneider C,Caroni P.Accumulation of SOD1mutants in postnatalmotoneurons does not cause motoneuron pathology or motoneuron disease. JNeurosci,2002,22:4825-4832
223.Boillee S,Yamanaka K,Lobsiger CS,Copeland NG,Jenkins NA,KassiotisG,et al.Onset and progression in inherited ALS determined by motor neuronsand microglia. Science,2006,312(5778):1389-1392
224.Fischer LR,Culver DG,Tennant P,Davis AA,Wang M,Castellano-SanchezA,et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence inmice and man. Exp Neurol,2004,185(2):232-240
225.Burke RE.Physiology of motor units. In: Engel, A.G., Franzini-Armstrong, C.(Eds.), Myology. McGraw-Hill, New York,1994, pp:464-484
226.Bommel H,Xie G,Rossoll W,Wiese S,Jablonka S,Boehm T,Sendtner M.Missense mutation in the tubulin-specific chaperone E (Tbce) gene in themouse mutant progressive motor neuronopathy,a model of humanmotoneuron disease. J Cell Biol,2002,159(4):563-569
227.Martin N,Jaubert J,Gounon P,Salido E,Haase G,Szatanik M,Guenet JL.Amissense mutation in Tbce causes progressive motor neuronopathy in mice.Nat Genet,2002,32(3):443-447
228.Sagot Y,Dubois-Dauphin M,Tan SA,de Bilbao F,Aebischer P,MartinouJC,Kato AC. Bcl-2overexpression prevents motoneuron cell body loss butnot axonal degeneration in a mouse model of a neurodegenerative disease. JNeurosci,1995,15(11):7727-7733
229.Hasbani DM,O’Malley KL.Wld(S) mice are protected against the Park-insonian mimetic MPTP. Exp Neurol,2006,202(1):93-99
230.Sajadi A,Schneider BL,Aebischer P. Wlds-mediated protection of dop-aminergic fibers in an animal model of Parkinson disease. Curr Biol,2004,14(4):326-330
231.Fischer LR, Culver DG, Davis AA, Tennant P,Wang M,et al. The WldS genemodestly prolongs survival in the SOD1G93A fALS mouse. Neurobiol Dis,2005,19(1-2):293-300
232.Ferri A,Sanes JR,Coleman MP,Cunningham JM,Kate AC..Inhibiting axondegeneration and synapse loss attenuates apoptosis and disease progressionin a mouse model of motoneuron disease. Curr. Biol,2003,13(8):669-673
233.Stokin GB,Goldstein LS.Axonal transport and Alzheimer’s disease.AnnuRev Biochem,2006,75:607-627
234.Stokin GB,Lillo C,Falzone TL,Brusch RG,Rockenstein E,Mount SL,etal.Axonopathy and transport deficits early in the pathogenesis ofAlzheimer’s disease. Science,2005,307(5713):1282-1288
235.Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronalviability by amyloid precursor protein mutations in Drosophila.Neuron,2001,32:389-401
236.Gunawardena S, Goldstein LS. Polyglutamine diseases and transport prob-lems: deadly traffic jams on neuronal highways.Arch Neurol,2005,62:46-51
237.Eaton BA,Fetter RD,Davis GW.Dynactin is necessary for synapsestabilization. Neuron,2002,34:729-741
238.Garcia-Fresco GP,Sousa AD,Pillai AM,Moy SS,Crawley JN,Tessarollo L, etal. Disruption of axo-glial junctions causes cytoskeletal disorganization anddegeneration of Purkinje neuron axons.Proc Natl Acad Sci USA,2006,103(13):5137-5142
239.Gotz J, Ittner LM, Kins S. Do axonal defects in tau and amyloid precursorprotein transgenic animals model axonopathy in Alzheimer’s disease?. JNeurochem,2006,98(4):993-1006
240.Delio DA, Fiori MG, Lowndes HE. Motor unit function during evolution ofproximal axonal swellings. J Neurol Sci,1992,109(1):30-40
241.Tsai J,Grutzendler J,Duff K,Gan WB.Fibrillar amyloid deposition leads tolocal synaptic abnormalities and breakage of neuronal branches.Nat Neurosci,2004,7(11):1181-1183
242.Mi W,Beirowski B,Gillingwate TH,Adalbert R,Wagner D,Grumme D,et al.The slow Wallerian degeneration gene,WldS,inhibits axonal spheroidpathology in gracile axonal dystrophy mice. Brain,2005,128(pt2):405-416
243.Pirozzi M,Quattrini A,Andolfi G,Dina G,Malaquti MC,Auricchio A,RuqarliEL.Intramuscular viral delivery of paraplegin rescues peripheral axonopathyin a model of hereditary spastic paraplegia.J Clin Invest,2006,116(1):202-208
244.Samsam M, Mi W, Wessig C, Zielasek J, Toyka KV, Coleman MP, MartiniR. The Wlds mutation delays robust loss of motor and sensory axons in agenetic model for myelin-related axonopathy. J Neurosci,2003,23(7):2833-2839
245.Zhang W, Qin LY,Wang TG, et al.32Hydroxymorphinan is neurotrophic todopaminergic neurons and is also neurop rotective against LPS inducedneurotoxicity. FASEB J,2005,19(4):395-397
246.Krieglstein K,Suter-Crazzolara C,Fischer WH and Unsicker K.TGF-βsuperfamily members promote survival of midbrain dopaminergic neuronsand protect them against MPP+toxicity.Eur molec Biol Org,1995,14:736-742
247.Dunnett SB,Bjorklund A.Prospects for new restorative and neuroprotectivetreatments in Parkinson’s disease.Nature,1999,399(6738Suppl):A32-39
248.Schober A.Classic toxin-induced animal models of Parkinson6-OHDA andMPTP.Cell Tissue Res,2004,318(1):215-224
249.Von Bohlen und Halbach O.Modeling neurodegenerative diseases in vivoreview.Neurodegener Dis,2005,2(6):313-320
250.Soderstrom K,O’Malley J,Steece-Collier K,et al.Neural repair strategies forParkinson’s disease:insights from primate models.Cell Transplant,2006,15(3):251-265
251.Cenci MA,Whishaw IQ,Schallert T.Animal models of neurological deficits:how relevant is the rat?.Nat Rev Neurosci,2002,3(7):574-579
252.Schober A.Classic toxin-induced animal models of Parkinson’s disease:6-OHDA and MPTP.Cell Tissue Res,2004,318(1):215-224
253.Schmidt N,Ferger B.Neurochemical findings in the MPTP model ofParkinson’s disease.J Neural Transm,2001,108(11):1263-1282
254.Jackson-Lewis V,Przedborski S.Protocol for the MPTP mouse model ofParkinson’s disease.Nat Protoc,2007,2(1):141-151
255.German DC,Nelson EL,Liang CL,et al.The neurotoxin MPTP causesdegeneration of specific nucleus A8,A9and A10dopaminergic neurons inthe mouse.Neurodegeneration,1996,5(4):229-312
256.Sedelis M,Schwarting RK,Huston JP.Behavioral phenotyping of the MPTPmouse model of Parkinson’s disease.Behav Brain Res,2001,125(1-2):109-125
257.Sundstrom E,Stromberg I,Tsutsumi T,et al.Studies on the effect of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)on central catecholamineneurons in C57BL/6mice.Comparison with three other strains of mice.BrainRes,1987,405(1):26-38
258.Bezard E,Dovero S,Bioulac B,et al.Effects of different schedules of MPTPadministration on dopaminergic neurodegeneration in mice.Exp Neurol,1997,148(1):288-292
259.Tillerson JL,Caudle WM,Reveron ME,et al.Exercise induces behavioralrecovery and attenuates neurochemical deficits in rodent models ofParkinson’s disease.Neuroscience,2003;119(3):899-911
260.Vila M,Vukosavic S,Jackson-Lewis V,et al.Alpha-synuclein up-regulation insubstantia nigra dopaminergic neurons following administration of theparkinsonian toxin MPTP.J Neurochem,2000,74(2):721-729
261.Storch A,Lester HA,Boehm BO,et al.Functional characterization ofdopaminergic neurons derived from rodent mesencephalic progenitor cells.JChem Neuroanat,2003,26(2):133
262.Carrasco E, Werner P.Selective destruction of dopaminergic neurons by lowconcentrations of6-OHDA and MPP+:protection by acetylsalicylic acid(aspirin).Parkinsonism and Related Disorders,2002,8:407-411
263.Yan-Yun Li,Jiang-Hai Lu, Quan Li,et al. Pedicularioside A from Buddleialindleyana inhibits cell death induced by1-methyl-4-phenylpyridinium ions(MPP+) in primary cultures of rat mesencephalic neurons.European Journalof Pharmacology,2008,579:134-140
264.Commissiong JW,Toffano G.The effect of GM-1ganglioside oncoerulospinal,noradrenergic adult neurons and on fetal monoaminerdicneurons transplanted into the transected spinal cord of the adult rat.BrainRes,1986,380:205-214
265.Araki T,Mikami T,Tanji H,Matsubara M,Imai Y,Mizuqaki M,ItoyamaY.Biochemical and immunohistological ehnages in the brain of l-methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP)-terated mouse. Eur J Pharm Sci,2001,12(3):231-238
266.Hofele K,Sedelis M,Aubugrer GW,Morgan S,Huston JP, Schwar rting RK.Evidence for a dissociation between MPTP toxicity and tytrosinase activitybased on congenic mouse strain susceptibility.Exp Neurol,2001,168(1):116-122
267.Seniuk NA,Tatton WG,Greenwood CE.Dose-dependent destruction of thecoeruleus-cortical and nigral-stratal projections by MPTP.Brain Res,1990,527(1):7-20
268.Hartley A,Stone JM,Heron C,Cooper JM,Schapira AH.Complex I inhibitorsinduce dose-dependent apoptosis in PC12cells:relevance to Parkinson’sdisease.J Neurochem,1994,63(5):1987-1990
269.Cochiolo JA,Ehsanian R,Bruck DK. Acute ultrastructural effects of MPTP onthe nigrostriatal pathway of the C57BL/6adult mouse:evidence ofcompensatory plasticity in nigrostriatal neurons.J Neurosci Res,2000,59(1):126-135
270.Gao HM,Hong JS,Zhang W,Liu B.Distinct role for microglia in rotenoneind-uced degeneration of dopaminergic neurons.J Neurosci,2002,22(3):782-790
271.Grammatopoulos TN,Ahmadi F,Jones SM,Fariss MW,Weyhenmeyer JA,Za-wada WM.Angiotensin II protects cultured midbrain dopaminergic neuronsagainst rotenone-induced cell death. Brain Res,2005,1045(1-2):64-71
272.Bruck W.The pathology of multiple sclerosis is the result of focalinflammatory demyelination with axonal damage. J Neurol,2005,252Suppl5:v3-v9
273.Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS:consequences for understanding the progressive phase of the disease. JNeurol Sci,2003,206(2):165-171
274.Brain dopamine and the syndromes of Parkinson and Huntington,Clinical,morphological and neurochemical correlations.J Neurol Sci,1973,20(4):415-455
275.Burns RS,Chiueh CC,Markey SP,Ebert MH,Jacobowitz DM,Kopin IJ.Aprimate model of parkinsonism:selective destruction of dopaminergicneurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Proc Natl Acad Sci USA,1983,80(14):4546-4550
276.Lach B,Grimes D,Benoit B,Minkiewicz-Janda A.Caudate nucleus pathologyin Parkinson's disease:ultrastructural and biochemical findings in biopsymaterial.Acta Neuropathol,1992,83(4):352-360
277.Saxena S,Caroni P. Mechanisms of axon degeneration:From development todisease. Prog Neurobiol,2007,83(3):174-191
278.Fischer LR, Glass JD. Axonal degeneration in motor neuron disease.Neurodegener Dis,2007,4(6):431-442
279.Sherriff FE,Bridges LR,Sivaloganathan S. Early Detection of Axonal Injuryafter Human Head Trauma using Immunocytochemist ry for Beta-amyloidPrecursor Protein. Acta Neuropathol (S0001-6322),1994;87(1):55-62
280.Blumbergs PC, Scott G, Manavis J,Wainwright H,Simpson DA,Mclean A.Topography of axonal injury as defined by amyloid precursor protein and thesector scoring method in mild and severe closed head injury. J Neurotrauma,1995,12(4):565-572
281.Stone JR, Singleton RH, Povlishock JT. Antibodies to the Cterminus of thebeta-amyloid precursor protein (APP): a site specific marker for the detectionof traumatic axonal injury. Brain Res,2000,871(2):288-302
282.刘洪恩,孙晓川. β-淀粉样前体蛋白与弥漫性轴索损伤.创伤外科杂志,2005,7(1):73-75
283.Loers G, Aboul-Enein F, Bartsch U,Lassmann H,Schcahner M. Comparisonof myelin, axon, lipid, and immunopathology in the central nervous systemof differentially myelin-compromised mutant mice: a morphological andbiochemical study. Mol Cell Neurosci,2004,27(2):175-189
284.Nogales E. Structural insights into microtubule function. Annu Rev Biochem,2000,69:277-302
285.Ren Y, Zhao J, Feng J. Parkin binds to alpha/beta tubulin and increases theirubiquitination and degradation. J Neurosci,2003,23(8):3316-3324
286.Feng J. Microtubule:a common target for parkin and parkinson’s diseasetoxins. Neuroscientist,2006,12(6):469-476
287.Cappelletti G,Pedrotti B,Maggioni MG,Maci R..Microtubule assembly isdirectly affected by MPP+in vitro.Cell Biol Int,2001,25(10):981-984
288.Cappelletti G, Surrey T, Maci R. The parkinsonism producing neurotoxinMPP+affects microtubule dynamics by acting as a destabilising factor. FEBSLett,2005,579(21):4781-4786
289.Coleman M. Axon degeneration mechanisms: commonality amid diversity.Nature reviews,Neuroscience.2005,6(11):889-898
290.Mimura F,Yamagishi S,Arimura N,Fujitani M,Kubo T,KaibuchiK,Yamasgita T.Myelin-associated glycoprotein inhibits microtubuleassembly by a Rho-kinase-dependent mechanism.J Biol Chem,2006,281(23):15970-15979
291.Uchida Y, Ohshima T, Sasaki Y, Suzuki S,Yamashita N,Nakamuta F,et al.Semaphorin3A signalling is mediated via sequential Cdk5and GSK3betaphosphorylation of CRMP2: implication of common phosphorylatingmechanism underlying axon guidance and Alzheimer's disease. Genes cells,2005,10(2):165-179
292.Youdim MB, Arraf Z. Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium:involvements of Bcl-2and Bax. Neuropharmacology,2004;46(8):1130-1140.
293.Xu J, Culman J, Blume A, Brecht S, Gohlke P. Chronic treatment with a lowdose of lithium protects the brain against schemic injury by reducingapoptotic death. Stroke,2003;34(5):1287-92.
294.Fujimura M, Usuki F, Kawamura M, Izumo S. Inhibition of the Rho/ROCKpathway prevents neuronal degeneration in vitro and in vivo followingmethylmercury exposure. Toxicol Appl Pharmacol,2011;250(1):1-9.
295.Manji HK, Chen G. PKC, MAP kinases and the bcl-2family of proteins aslong-term targets for mood stabilizers. Mol Psychiatry,2002;7Suppl1:S46-S56.
296.Manji HK, Moore GJ, Chen G. Lithium at50: have the neuroprotectiveeffects of this unique cation been overlooked?.Biol Psychiatry,1999;46(7):929-940.
297.Nonaka S, Chuang DM. Neuroprotective effects of chronic lithium on focalcerebral ischemia in rats. Neuroreport,1998;9(9):2081-2084.
298.Chen G, Zeng WZ, Yuan PX, Huang LD,Jiang YM,Zhao ZH,Manji HK. Themood-stabilizing agents lithium and valproate robustly increase the levelsofthe neuroprotective protein bcl-2in the CNS. J Neurochem,1999;72(2):879-882.
299.Chen RW, Chuang DM. Long term lithium treatment suppresses p53andBax expression but increases Bcl-2expression:A prominent role in neuro-protection against excitotoxicity. J Biol Chem,1999;274(10):6039-6042.
300.Chalecka-Franaszek E, Chuang DM. Lithium activates the serine/threoninekinase Akt-1and suppresses glutamate-induced inhibition of Akt-1activityin neurons. Proc Natl Acad Sci USA,1999:96(15):8745-8750.
301.Martin L,Magnaudeix A,Esclaire F,Yardin C,Terro F.Inhibition of glycogensynthase kinase-3β down regulates total tau proteins in cultured neurons andits reversal by the blockade of preotein phosphatase-2α.Brain Res,2009;1252:66-75
302.Goverk EE,Newey SE,Van Aelst L.The role of the Rho GTPases in neuronaldevelopment.Genes Dev,2005,19(1):1-49
303.Sasaki Y, Suzuki M, Hidaka H. The novel and specific Rho-kinaseinhibitor(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol.Ther,2002;93(2-3):225-232.
304.Mukai H. The structure and function of PKN, a protein kinase having acatalytic domain homologous to that of PKC.J Biochem,2003;133(1):17-27.
305.Janeczek AH,Van Alten PJ,Reyes HM,Walter RJ.Modulation of thecytoskeleton and intracellular calcium in leukocyte exhibiting acancer-associated chemotaxis defect. J Leukoc Biol,1993;54(4):351-359.
2. De Rijk MC, Breteler MM, Graveland GA, Ott A, Grobbee DE, van derMeche FG, Hofman A. Prevalence of Parkinson's disease in the elderly: theRotterdam Study. Neurology,1995,45(12):2143-2146
3. Tanner CM, Ottman R, Goldman SM, et al.Parkinson disease in twins: anetiologic study. JAMA,1999,281(4):341-346
4. Zhang J, Perry G, Smith MA, Robertson D,Olson SJ,et al. Parkinson’sdisease is associated with oxidative damage to cytoplasmic DNA and RNAin substantia nigra neurons. Am J Pathol,1999,154(5):1423-1429
5. Zigmond MJ.When it comes to communications between neurons,synapsesare over-rated: insights from an animal model of parkinsonism.Prog BrainRes,2000,125:317-326
6. Kieburtz K,Ravina B. Why hasn't neuroprotection worked in Parkinson'sdisease. Nature Clinical Practice Neurology,2007,3(5):240-241
7. Steward O, Zheng B, Tessier-Lavigne M. False resurrections: distinguishingregenerated from spared axons in the injured central nervous system. J CompNeurol,2003,459(1):1-8
8. Saxena S, Caroni P. Mechanisms of axon degeneration: from development todisease. Prog Neurobiol,2007,83(3):174-191
9. Luo L, O'Leary D.D. Axon retraction and degeneration in development anddisease. Annu Rev Neurosci,2005,28:127-156
10. John ED, Benoilt IG, Virginia M-Y, et al. Is the Initial Insult in Parkinson'sDisease and Dementia with Lewy Bodies a Neuritic Dystrophy?PARKINSON'S DISEASE: The Life Cycle of the Dopamine Neuron-AnnNY Acad Sci,2003,991:295-297
11. Conforti L,Adalbert R,Coleman MP. Neuronal death:where does the endbegin. Trends Neurosci,2007,30(4):159-166
12. Sajadi A,Schneider BL,Aebischer P.Wlds-mediated protection of dopam-inergic fibers in an animal model of Parkinson disease. Current biology: CB,2004,14(4):326-330
13.姚庆和,高国栋.肌苷对帕金森病小鼠模型的神经保护作用.第四军医大学学报,2005,26(2):141-144
14. Dauer W,Przedborski S.Parkinson’s disease: mechanisms and models.Neuron,2003,39(6):889-909
15. Samii A,Nutt JG,Ransom BR.Parkinson’s disease.Lancet,2004,363:1783-1793
16. Moore DJ,West AB,Dawson VL,Dawson TM. Molecular pathophysiology ofParkinson’s disease. Annu Rev Neurosci,2005,28:57-87
17. Riess O, Kruger R, Hochstrasser H, Soehn AS, Nuber S, Franck T,BergD.Genetic causes of Parkinson’s disease: extending the pathway. JNeural Transm Suppl,2006,70:181-189
18. Vila M,Przedborski S.Genetic clues to the pathogenesis of Parkinson’sdisease. Nat Med (Suppl.),2004,10: S58-62
19. Bonifati V,Rizzu P, van Baren MJ,Schaap O,Breedveld GJ,KriegerE,DekkerMC, Squitieri F,et al.Mutations in the DJ-1gene associated with autosomalrecessive early-onset parkinsonism.Science,2003,299(5604):256-259
20. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S,Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene causeautosomal recessive juvenile Parkinsonism. Nature,1998,392(6676):605-608
21. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S,Ali Z, Del Turco D,et al. Hereditary early-onset Parkinson’s disease causedby mutations in PINK1. Science,2004,304(5674):1158-1160
22. Farrer MJ.Genetics of Parkinson disease: paradigm shifts and futureprospects.Nat Rev Genet,2006,7(4):306-318
23. Le W,Appel SH. Mutant genes responsible for Parkinson’s disease. CurrOpin Pharmacol,2004,4(1):79-84
24. Kruger R,Kuhn W,Muller T,Woitalla D, Graeber M, K sel S, Przuntek H, etal.Ala30Promutation in the gene encoding alpha-synuclein in Parkinson’sdisease. Nat Genet,1998,18(2):106-108
25. Paisan-Ruiz C,Jain S, Evans EW,Gilks WP,Simón J, van der Brug M, Lópezde Munain A, et al.Cloning of the gene containing mutations that causePARK8-linked Parkinson’s disease. Neuron,2004,44(4):595-600
26. Polymeropoulos MH, Lavedan C,Leroy E,Ide SE, Dehejia A, Dutra A, PikeB, et al.Mutation in the alpha-synuclein gene identified in families withParkinson’s disease. Science,1997,276(5321):2045-2047
27. Singleton AB,Farrer M,Johnson J,Singleton A, Hague S, Kachergus J, et al.Alpha-synuclein locus triplication causes Parkinson’s disease. Science,2003,302(5646):841
28. Zimprich A,Biskup S,Leitner P,Lichtner P,Farrer M,Lincoln S,et al.Mutations in LRRK2cause autosomal-dominant parkinsonism withpleomorphic pathology. Neuron,2004,44(4):601-607
29. Le WD,Xu P,Jankovic J,Jiang H,Appel SH,Smith RG,Vassilatis DK,Mutations in NR4A2associated with familial Parkinson disease. NatGenet,2003,33(1):85-89
30. Leroy E,Boyer R,Auburger G,Leube B, Ulm G, Mezey E,et al. The ubiquitinpathway in Parkinson’s disease. Nature,1998,395(6701):451-452
31. Marx FP, Holzmann C, Strauss KM, Li L, Eberhardt O, Gerhardt E, CooksonMR,et al. Identification and functional characterization of a novel R621Cmutation in the synphilin-1gene in Parkinson’s disease.Hum MolGenet,2003,12(11):1223-1231
32. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D,et al. Loss of function mutations in the gene encoding Omi/HtrA2inParkinson’s disease. Hum Mol Genet.2005,14(15):2099-2111
33. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP,Goebel I,et al. Hereditary parkinsonism with dementia is caused bymutations in ATP13A2, encoding a lysosomal type5P-type ATPase. NatGenet,2006,38(10):1184-1191
34. Gasser T, Muller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, BonifatiV, et al. A susceptibility locus for Parkinson’s disease maps to chromosome2p13. Nat Genet,1998,18(3):262-265
35. Hicks AA,Petursson H,Jonsson T, Stefansson H,Johannsdottir HS,et al. Asusceptibility gene for late-onset idiopathic Parkinson’s disease. AnnNeurol,2002,52(5):549-555
36. Pankratz N, Nichols WC, Uniacke SK,Halter C,Murrell J,Rudolph A, et al.Genome-wide linkage analysis and evidence of gene-by-gene interactions ina sample of362multiplex Parkinson disease families. Hum MolGenet,2003,12(20):2599-2608
37. Pankratz N, Nichols WC, Uniacke SK, Halter C,Rudolph A,et al. Significantlinkage of Parkinson disease to chromosome2q36-37. Am J HumGenet2003,72(4):1053-1057
38. Farrer MJ.Genetics of Parkinson disease: paradigm shifts and futureprospects.Nat Rev Genet,2006,7:306-318
39. Farrer M, Maraganore DM, Lockhart P, Singleton A,Lesnick TG,de AndradeM,et al. Alpha-synuclein gene haplotypes are associated with Parkinson’sdisease. Hum Mol Genet,2001,10(17):1847-1851
40. Kruger R,Vieira-Saecker AM, Kuhn W, Berg D,Muhnl N,Fuchs GA,et al.Increased susceptibility to sporadic Parkinson’s disease by a certaincombined alpha-synuclein/apolipoprotein E genotype. Ann Neurol,1999,45(5):611-617
41. Maraganore DM, Farrer MJ, Hardy JA, Lincoin SJ,et al. Case-control studyof the ubiquitin carboxy-terminal hydrolase L1gene in Parkinson’s disease.Neurology,1999,53(8):1858-1860
42. Satoh J, Kuroda Y.A polymorphic variation of serine to tyrosine at codon18in the ubiquitin C-terminal hydrolase-L1gene is associated with a reducedrisk of sporadic Parkinson’s disease in a Japanese population. J Neurol Sci,2001,189(1-2):113-117
43. Davis GC, Williams AC, Markey SP,Ebert MH,Caine ED,et al. ChronicParkinsonism secondary to intravenous injection of meperidine analogues.Psychiatry Res,1979,1(3):249-254
44. Langston JW,Ballard Jr PA.Parkinson’s disease in a chemist working with1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.N Engl J Med,1983,309(5):310
45. Davis GC, Williams AC, Markey SP, Ebert MH,Caine ED,et al. ChronicParkinsonism secondary to intravenous injection of meperidine analogues.Psychiatry Res,1979,1(3):249-254
46. Burns RS, Chiueh CC, Markey SP, Ebert MH,Jacobowitz DM,Kopin IJ.Aprimate model of parkinsonism: selective destruction of dopaminergicneurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA,1983,80(14):4546-4550
47. Johansson B, Roos BE.5-Hydroxyindoleacetic and homovanillic acid levelsin the cerebrospinal fluid of healthy volunteers and patients with Parkinson’ssyndrome. Life Sci,1967,6:1449-1454
48. Olsson R, Roos BE. Concentrations of5-hydroxyindoleacetic acid andhomovanillic acid in the cerebrospinal fluid after treatment with probenecidin patients with Parkinson’s disease. Nature,1968,219:502-503
49. Heikkila RE,Manzino L,Cabbat FS,Duvoisin RC. Protection against thedopaminergic neurotoxicity of1-methyl-4-phenyl-1,2,5,6-tetrahydropyridineby monoamine oxidase inhibitors. Nature,1984,311(5985):467-469
50. Langston JW, Irwin I, Langston EB, Forno LS. Pargyline prevents MPTPinduced parkinsonism in primates. Science,1984,225(4669):1480-1482
51. Markey SP,Johannessen JN,Chiueh CC,Burns RS,Herkenham MA.Intraneuronal generation of a pyridinium metabolite may cause drug-inducedparkinsonism. Nature,1984,311(5985):464-467
52. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH.Parkinsonisminducingneurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of themetabolite N-methyl-4-phenylpyridine by dopamine neurons explainsselective toxicity. Proc Natl Acad Sci USA,1985,82(7):2173-2177
53. Chiba K, Trevor A, Castagnoli N Jr. Metabolism of the neurotoxic tertiaryamine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun,1984,120(2):574-578
54. Heikkila RE, Nicklas WJ, Duvoisin RC. Dopaminergic toxicity after thestereotaxic administration of the1-methyl-4-phenylpyridinium ion (MPP+)to rats. Neurosci Lett,1985,59(1):135-140
55. Nicklas WJ,Vyas I,Heikkila RE.Inhibition of NADH-linked oxidation inbrain mitochondria by1-methyl-4-phenyl-pyridine,a metabolite of theneurotoxin,1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.Life Sci,1985,36(26):2503-2508
56. Bindoff LA,Birch-Machin M,Cartlidge NE, Parker WD Jr,TurnbullDMMitochondrial function in Parkinson’s disease. Lancet,1989,2(8653):49
57. Bindoff LA, Birch-Machin M, Cartlidge NE, Parker WD Jr,Turnbull DM.Respiratory chain abnormalities in skeletal muscle from patients withParkinson’s disease. J Neurol Sci,1991,104(2):203-208
58. Parker Jr WD, Boyson SJ, Parks JK. Abnormalities of the electron transportchain in idiopathic Parkinson’s disease. Ann Neurol,1989,26:719-723
59. Schapira AH,Cooper JM,Dexter D,Clark JB,Jenner P,Marsden CD.Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem,1990,54(3):823-827
60. Hartley A,Stone JM,Heron C,Cooper JM,Schapira AH. Complex I inhibitorsinduce dose-dependent apoptosis in PC12cells: relevance to Parkinson’sdisease. J Neurochem,1994,63(5):1987-1990
61. McNaught KS, Thull U, Carrupt PA, Altomare C,Cellamare S,Carotti A,et al.Inhibition of complex I by isoquinoline derivatives structurally related to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem Pharmacol,1995,50(11):1903-1911
62. McNaught KS, Thull U, Carrupt PA, Altomare C, Cellamare S, Carotti A,Testa B, et al. Effects of isoquinoline derivatives structurally related to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrialrespiration. Biochem Pharmacol,1996,51(11):1503-1511
63. McNaught KS,Thull U,Carrupt PA, Altomare C, Cellamare S, Carotti A,Testa B, Jenner P, Marsden CD.Toxicity to PC12cells of isoquinolinederivatives structurally related to1-methyl-4-phenyl-1,2,3,6-tetrahydropy-ridine. Neurosci Lett,1996,206(1):37-40
64. Seaton TA,Cooper JM,Schapira AH.Free radical scavengers protect do-paminergic cell lines from apoptosis induced by complex I inhibitors. BrainRes,1997,777(1-2):110-118
65. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV, GreenamyreJT.Chronic systemic pesticide exposure reproduces features of Parkinson’sdisease. Nat Neurosci,2000,3(12):1301-1306
66. McNaught KS, Thull U, Carrupt PA, Altomare C,Cellamare S,Carotti A,et al.Nigral cell loss produced by infusion of isoquinoline derivatives structurallyrelated to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration,1996,5(3):265-274
67. Yoshida M,Niwa T,Nagatsu T.Parkinsonism in monkeys produced bychronic administration of an endogenous substance of the brain, tetrahydro-isoquinoline: the behavioral and biochemical changes. Neurosci Lett,1990,119(1):109-113
68. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV,Greenamyre JT.Chronic systemic pesticide exposure reproduces features ofParkinson’s disease. Nat Neurosci,2000,3(12):1301-1306
69. Ferrante RJ, Schulz JB, Kowall NW, Beal MF.Systemic administration ofrotenone produces selective damage in the striatum and globus pallidus, butnot in the substantia nigra. Brain Res,1997,753(1):157-162
70. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV, GreenamyrJT.Chronic systemic pesticide exposure reproduces features of Parkinson’sdisease. Nat Neurosci,2000,3(12):1301-1306
71. Lai BC,Marion SA,Teschke K, Tsui JK. Occupational and environmentalrisk factors for Parkinson’s disease. Parkinsonism Relat. Disord,2002,8:297-309
72. Young AB, Penney JB. Biochemical and functional organization of the basalganglia, in: J. Jankovic, E. Tolosa (Eds.), Parkinson’s Disease and MovementDisorders, Williams and Wilkins, Baltimore,1993, pp.1-11
73. German DC,Manaye K,Smith WK,Woodward DJ,Saper CB.Midbraindopaminergic cell loss in Parkinson’s disease: computer visualization. AnnNeurol,1989,26(4):507-514
74. Ma Y, Dhawan V, Mentis M, Chaly T, Spetsieris PG,Eidelberg D.Parametric mapping of [18F]FPCIT binding in early stage Parkinson’sdisease: a PET study.Synapse,2002,45(2):125-133
75. Damier P,Hirsch EC,Agid Y,Graybiel AM. The substantia nigra of thehuman brain:II Patterns of loss of dopamine-containing neurons inParkinson’s disease. Brain,1999,122(pt8):1437-1448
76. Nurmi E,Ruottinen HM,Bergman J,Haaparanta M,Solin O,et al.Rate ofprogression in Parkinson’s disease:a6-[18F]fluoro-l-dopa PET study.MovDisord,2001,16(4):608-615
77. Di Monte DA.The environment and Parkinson’s disease:is the nigrostriatalsystem preferentially targeted by neurotoxins?.Lancet Neurol,2003,2(9):531-538
78. Steece-Collier K,Maries E,Kordower JH.Etiology of Parkinson’s disease:genetics and environment revisited, Proc Natl Acad Sci USA,2002,99(22):13972-13974
79. Payami H,Zareparsi S.Genetic epidemiology of Parkinson’s disease.J GeriatrPsychiatry Neurol,1998,11(2):98-106
80. Burke RE.Recent advances in research on Parkinson disease:synuclein andparkin.Neurologist,2004,10(2):75-81
81. Hu CJ,Sung SM,Liu H,Chang JG.No mutation of G209A in the alpha-synuclein gene in sporadic Parkinson’s disease among Taiwan Chinese.EurNeurol,1999,41(2):85-87
82. Scott WK, Yamaoka LH, Stajich JM, et al.The alphasynuclein gene is not amajor risk factor in familial Parkinson disease.Neurogenetics,1999,2:191-192
83. Brecknell JE, Dunnett SB, Fawcett JW. A quantitative study of cell death inthe substantia nigra following a mechanical lesion of the medial forebrainbundle. Neuroscience,1995,64(1):219-227
84. Faull RL, Mehler WR.The cells of origin of nigrotectal,nigrothalamic andnigrostriatal projections in the rat. Neuroscience,1978,3(11):989-1002
85. Deumens R, Blokland A, Prickaerts J. Modeling Parkinson’s disease in rats:an evaluation of6-OHDA lesions of the nigrostriatal pathway. Exp Neurol,2002,175(2):303-317
86. Hirsch EC,Hoglinger G,Rousselet E, Breidert T,Parain K,et al.Animalmodels of Parkinson’s disease in rodents induced by toxins:an update.JNeural Transm Suppl,2003,(65):89-100
87. Olney JW,Zorumski CF,Stewart GR,Price MT,Wang GJ,Labruyere J.Excitotoxicity of L-dopa and6-OH-dopa:implications for Parkinson’s andHuntington’s diseases. Exp Neurol,1990,108(3):269-272
88. Burns RS,LeWitt PA,Ebert MH,Pakkenberg H,Kopin IJ.The clinicalsyndrome of striatal dopamine deficiency; parkinsonism induced by MPTP.N Engl J Med,1985,312(22):1418-1421
89. Langston JW.The case of the tainted heroin. Sciences,1985,25:34-40
90. Langston JW, Palfreman J. The Case of the Frozen Addicts.Vintage Books,New York,1996
91. Jenner P.The contribution of the MPTP-treated primate model to thedevelopment of new treatment strategies for Parkinson’s disease.Parkinsonism Relat Disord,2003,9(3):131-137
92. Kopin IJ, Markey SP.MPTP toxicity:implications for research in Parkinson’sdisease, Annu Rev Neurosci,1988,11:81-96
93. Wichmann T,DeLong MR.Pathophysiology of Parkinson’s disease:theMPTP primate model of the human disorder.Ann N Y Acad Sci,2003,991:199-213
94. Hamre K,Tharp R,Poon K,Xiong X,Smeyne RJ.Differential strain suscepti-bility following1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) admi-nistration acts in an autosomal dominant fashion: quantitative analysis inseven strains of Mus musculus.Brain Res.1999,828(1-2):91-103
95. Mitra N,Mohanakumar KP,Ganguly DK.Resistance of golden hamster to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: relation-ship with low levelsof regional monoamine oxidase B.J Neurochem,1994,62:1906-1912
96. Riachi NJ,Harik SI. Strain differences in systemic1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in mice correlate best with monoamineoxidase activity at the blood-brain barrier.Life Sci,1988,42:2359-2363
97. Betarbet R,Sherer TB,MacKenzie G,Garcia-Osuna M,Panov AV,Greenamyre JT.Chronic systemic pesticide exposure reproduces features ofParkinson’s disease.Nat Neurosci,2000,3(12):1301-1306
98. Brooks AI,Chadwick CA,Gelbard HA,Cory-Slechta DA,Federoff HJ.Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuronloss. Brain Res,1999,823(1-2):1-10
99. Chun HS,Gibson GE,DeGiorgio LA, Zhang H,Kidd VJ,SonJH.Dopaminergic cell death induced by MPP(+), oxidant and specificneurotoxicants shares the common molecular mechanism. J Neurochem,2001,76(4):1010-1021
100. Thiruchelvam M,Richfield EK,Baggs RB,Tank AW,Cory-Slechta DA..Thenigrostriatal dopaminergic system as a preferential target of repeatedexposures to combined paraquat and maneb:implications for Parkinson’sdisease.J Neurosci,2000,20(24):9207-9214
101.Kalaria RN, Mitchell MJ, Harik SI. Correlation of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood–brain barrier monoamineoxidase activity. Proc Natl Acad Sci U S A,1987,84:3521-3525
102.Riachi NJ, Harik SI, Kalaria RN, Savre LM. On the mechanisms underlying1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: II Susceptibilityamong mammalian species correlates with the toxin’s metabolic patterns inbrain microvessels and liver, JPET,1988,244(2)443-448
103.Riachi NJ,Dietrich WD,Harik SI. Effects of internal carotid administration ofMPTP on rat brain and blood-brain barrier, Brain Res,1990,533(1):6-14
104.Brooks WJ,Jarvis MF,Wagner GC. Astrocytes as a primary locus for theconversion MPTP into MPP+. J Neural Transm,1989,76(1):1-12
105.Hazell AS,Itzhak Y,Liu H,Norenberg MD.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreases glutamate uptake in culturedastrocytes. J Neurochem,1997,68(5):2216-2219
106.Kopin IJ.Features of the dopaminergic neurotoxin MPTP. Ann NY AcadSci,1992,648:96-104
107.Marini AM,Lipsky RH,Schwartz JP,Kopin IJ.Accumulation of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in cultured cerebellar astrocytes.JNeurochem,1992,58(4):1250-1258
108.Teismann P,Tieu K,Cohen O,Choi DK,Wu DC,Marks D,et al.Pathogenicrole of glial cells in Parkinson’s disease.Mov Disord,2003,18(2):121-129
109.Ofori S,Schorderet M.Effects of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopamine synthesis and release in the rabbit retina in vitro.Neuropharmacology,1987,26:1607-1610
110.Hunot S,Dugas N,Faucheux B,Hartmann A,Tardieu M,Debre P,et al.FcepsilonRII/CD23is expressed in Parkinson’s disease and induces, in vitro,production of nitric oxide and tumor necrosis factor-alpha in glial cells. JNeurosci,1999,19(9):3440-3447
111.Muramatsu Y,Kurosaki R,Watanabe H,Michimata M,Matsubara M,ImaiY,Araki T.Cerebral alterations in a MPTP-mouse model of Parkinson’sdisease-an immunocytochemical study.J Neural Transm,2003,110(10):1129-1144
112.Przedborski S,Jackson-Lewis V,Yokoyama R,Shibata T,Dawson VL,Dawson TM. Role of neuronal nitric oxide in1-methyl-4-phenyl-1,2,3,6-tetrahy dropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc NatlAcad Sci U SA,1996,93(10):4565-4571
113.Knott C,Stern G,Wilkin GP. Inflammatory regulators in Parkinson’s disease:iNOS,lipocortin-1and cyclooxygenases-1and-2.Mol Cell Neurosci,2000,16:724-739
114.Liberatore GT,Jackson-Lewis V,Vukosavic S,Mandir AS,Vila M,etal.Inducible nitric oxide synthase stimulates dopaminergic neurodegenerationin the MPTP model of Parkinson disease. Nat Med,1999,5(12):1403-1409
115.Wu DC,Jackson-Lewis V,Vila M,Tieu K,Teismann P,Vadseth C,et al.Blockade of microglial activation is neuroprotective in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. JNeurosci,2002,22(5):1763-1771
116.Kitayama S,Wang JB,Uhl GR.Dopamine transporter mutants selectivelyenhance MPP+transport.Synapse,1993,15:58-62
117.Smeyne M, Goloubeva O, Smeyne R.J.Strain-dependent susceptibility toMPTP and MPP+-induced Parkinsonism is determined by glia. Glia,2001,74:73-80
118.Di Monte DA,Wu EY,Irwin I,Delanney LE,Langston JW.Production anddisposition of1-methyl-4-phenylpyridinium in primary cultures of mouseastrocytes. Glia,1992,5(1):48-55
119.Di Monte DA, Royland JE, Irwin I, Langston JW.Astrocytes as the site forbioactivation of neurotoxins. Neurotoxicology,1996,17(3-4):697-703
120.McGeer PL, McGeer EG.Glial cell reactions in neurodegenerative diseases:pathophysiology and therapeutic interventions, Alzheimer Dis AssocDisord,1998,12(Suppl.2):S1-S6
121.McNaught, KSP, Jenner P. Altered glial function causes neuronal death andncreases neuronal susceptibility to1-methyl-4-phenylpyridinium-and6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalicco-cultures.J Neurochem,1999,73:2469-2476
122.Kienzl E,Jellinger K,Stachelberger H,Linert W.Iron as catalyst for oxidativestress in the pathogenesis of Parkinson’s disease? Lif Sci,1999,65:1973-1976
123.Schipper HM, Liberman A,Stopa EG.Neural heme oxygenase-1expressionin idiopathic Parkinson’s disease. Exp Neurol,1998,150:60-68
124.Fernandez-Gonzales A,Perez-Otano I,Morgan JI. MPTP selectively inducesheme oxygenase-1expression in striatal astrocytes.Eur J Neurosci,2000,12:1573-1583
125.Poss KD,Tonegawa S.Heme oxygenase1is required for mammalian ironreutilization. Proc Natl Acad Sci U S A,1997,94:10919-10924
126.Maines MD. The heme oxygenase system: a regulator of second messengergases. Annu Rev Pharmacol Toxicol,1997,37:517-554
127.Dringen R, Pfeiffer B, Hamprecht B.Synthesis of the antioxidant glutathionein neurons: supply by astrocytes of CysGly as precursor for neuronalglutathione.J Neurosci,1999,19:562-569
128.Hatakeyama S,Hayasaki Y,Masuda M, Kazusaka A,Fujita S.Mechanism formouse strain differences in the protective effect of sudan III against the invivo genotoxicity of7,12-dimethylbenz[a]anthracene.Toxicol Lett,1996,89(3):231-239
129.Schaar DG,Sieber BA,Dreyfus CF,Black IB. Regional and cell-specificexpression of GDNF in rat brain. Exp Neurol,1993,124(2):368-371
130.Schaar DG,Sieber BA,Sherwood AC,Dean D,Mendoza G,et al.Multipleastrocyte transcripts encode nigral trophic factors in rat and human.ExpNeurol,1994,130(2):387-393
131.Gong L,Wyatt RJ,Baker I,Masserano JM.Brain-derived and glial cellline-derived neurotrophic factors protect a catecholaminergic cell line fromdopamine-induced cell death.Neurosci Let,1999,263:153-156
132.Kirschner PB, Jenkins BG, Schulz JB,Frnkelstein SP,Matthews RT,et al.NGF, BDNF and NT-5, but not NT-3protect against MPP+toxicity andoxidative stress in neonatal animals. Brain Res,1996,713(1-2):178-185
133.Petersen AA,Larsen KE,Behr GG,Romero N, Przedborski S, BrundinP,Sulzer D..Brain-derived neurotrophic factor inhibits apoptosis anddopamine-induced free radical production in striatal neurons but does notprevent cell death. Brain Res Bull,2001,56(3-4):331-335
134.Heaton MB, Paiva M, Madorsky I, Mayer J,Moore DB.Effects of ethanol onneurotrophic factors, apoptosis-related proteins,endogenous antioxidants, andreactive oxygen species in neonatal striatum: relationship to periods ofvulnerability. Brain Res Dev Brain Res,2003,140(2):237-252
135.Schabitz WR,Sommer C,Zoder W,Kiessling M,Schwaninger M,SchwabS.Intravenous brain-derived neurotrophic factor reduces infarct size andcounterregulates bax and bcl-2expression after temporary focal cerebralischemia. Stroke,2000,31(9):2212-2217
136.Lander ES,Schork NJ.Genetic dissection of complex traits.Science.1994,265:2037-2048[published erratum appears in Science1994Oct21;266(5184):353]
137.Del Zompo M,Piccardi MP,Ruiu S,Quartu M,Gessa GL,Vaccari A.SelectiveMPP+uptake into synaptic dopamine vesicles:possible involvement in MPTPneurotoxicity.Br J Pharmacol,1993,109(2):411-414
138.Ramsay RR,Singer TP.Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria.J Biol Chem,1986,261:7585-7587
139.Ramsay RR,Dadgar J,Trevor A,Singer TP.Energy-driven uptake of N-methyl-4-phenylpyridine by brain mitochondria mediates the neuro-toxicity ofMPTP. Life Sci,1986,39(7):581-588
140.Mizuno Y, Sone N, Suzuki K, Saitoh T. Studies on the toxicity of1-methyl-4-phenylpyridinium ion (MPP+) against mitochondria of mouse brain.JNeurol Sci,1988,86:97-110
141.Beal MF.Mitochondria, oxidative damage, and inflammation in Parkinson’sdisease. Ann NY Acad Sci,2003,991:120-131
142.Muller T,Buttner T,Gholipour AF,Kuhn W.Coenzyme Q10supple-mentation provides mild symptomatic benefit in patients with Parkinson’sdisease. Neurosci Lett,2003,341(3):201-204
143.Cleeter MW,Cooper JM,Schapira AH.Irreversible inhibition of mitochon-drial complex I by1-methyl-4-phenylpyridinium: evidence for free radicalinvolvement. J Neurochem,1992,58:786-789
144.Przedborski S,Kostic V,Jackson-Lewis V,Naini AB,Simonetti S,et al.Transgenic mice with increased Cu/Zn–superoxide dismutase activity areresistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuro-toxicity. J Neurosci,1992,12(5):1658-1667
145.Wu DC,Teismann P,Tieu K,Vila M,Jackson-Lewis V,et al.NADPH oxidasemediates oxidative stress in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease.Proc Natl Acad Sci U S A,2003,100(10):6145-6150
146.Radi R,Cassina A,Hodara R,Quijano C,Castro L.Peroxynitrite reactions andformation in mitochondria.Free Radic Biol Med,2002,33:1451-1464
147.Hamre K,Tharp R,Poon K,Xiong X,Smeyne RJ.Differential strainsusceptibility following1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)administration acts in an autosomal dominant fashion:quantitative analysis inseven strains of Mus musculus.Brain Res,1999,828(1-2):91-103
148.Kuhn DM,Aretha CW,Geddes TJ.Peroxynitrite inactivation of tyrosinehydroxylase:mediation by sulfhydryl oxidation, not tyrosine nitration.JNeurosci,1999,19:10289-10294
149.Ara J,Przedborski S,Naini AB,Jackson-Lewis V,Trifiletti RR,et al.Inactivation of tyrosine hydroxylase by nitration following exposure toperoxynitrite and1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Proc Natl Acad Sci U S A,1998,95(13):7659-7663
150.Liberatore GT,Jackson-Lewis V,Vukosavic S,Mandir AS,Vila M,etal.Inducible nitric oxide synthase stimulates dopaminergic neurodegen-eration in the MPTP model of Parkinson disease.Nat Med,1999,5(12):1403-1409
151.Slivka A,Cohen G.Hydroxyl radical attack on dopamine.J Biol Chem,1985,260:15466-15472
152.Hirrlinger J, Schulz JB, Dringen R. Effects of dopamine on the glutathionemetabolism of cultured astroglial cells: implications for Parkinson’s disease.J Neurochem,2002,82:458-467
153.LaVoie MJ, Hastings TG.Peroxynitrite-and nitrite-induced oxidation ofdopamine: implications for nitric oxide in dopaminergic cell loss.JNeurochem,1999,73:2546-2554
154.Graham DG.Oxidative pathways for catecholamines in the genesis ofneuromelanin and cytotoxic quinones. Mol Pharmacol,1978,14:633-643
155.Hastings TG.Enzymatic oxidation of dopamine: the role of prostaglandin Hsynthase. J Neurochem,1995,64:919-924
156.O’Banion MK. COX-2and Alzheimer’s disease: potential roles in inflam-mation and neurodegeneration. Expert Opin Investig Drugs,1999,8:1521-1536
157.Teismann P,Tieu K,Choi DK,Wu DC,Naini A,Hunot S, et al. Cyclooxy-genase-2is instrumental in Parkinson’s disease neurodegeneration. Proc NatlAcad Sci U S A,2003,100(9):5473-5478
158.Miller GW,Erickson JD,Perez JT,Penland SN,Mash DC,Rye DB,LeveyAL.Immunochemical analysis of vesicular monoamine transporter (VMAT2)protein in Parkinson’s disease.Exp Neurol,1999,156(1):138-148
159.Gainetdinov RR,Fumagalli F,Wang YM,Jone SR,Levey AL,MillerGW,Caron MG.Increased MPTP neurotoxicity in vesicular monoaminetrans porter2heterozygote knockout mice. J Neurochem,1998,70(5):1973-1978
160.Takahashi N, Miner LL,Sora I,Ujike H,Revay RS,Kostic V, et al.VMAT2knockout mice:heterozygotes display reduced amphetamine-conditionedreward,enhanced amphetamine locomotion,and enhanced MPTPtoxicity.Proc Natl Acad Sci U S A,1997,94(18):9938-9943
161.Liu Y,Peter D,Roghani A,Schuldiner S,Prive GG,Eisenberg D,et al.A cDNAthat suppresses MPP+toxicity encodes a vesicular amine transporter.Cell,1992,70(4):539-551
162.Schluter OM,Fornai F,Alessandri MG,Takamori S,Geppert M,Jahn R,SudhofTC.Role of alpha-synuclein in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.Neuroscience,2003,118(4):985-1002
163.Conway KA, Harper JD, Lansbury PT.Accelerated in vitro fibril formationby a mutant alpha-synuclein linked to early-onset Parkinson disease.Nat Med,1998,4:1318-1320
164.Ischiropoulos H, al-Mehdi AB.Peroxynitrite-mediated oxidative proteinmodifications. FEBS Lett,1995,364:279-282
165.Giasson BI,Duda JE,Murray IV,Chen Q,SouzaJM,Hurtiq HI,IschiropoulosH,et al. Oxidative damage linked to neurodegeneration by selectivealphasynuclein nitration in synucleinopathy lesions.Science,2000,290(5493):985-989
166.Giasson BI,Jakes R,Goedert M,Duda JE,Leiqht S,Trojanowski JQ,Lee VM.Apanel of epitope-specific antibodies detects protein domains distributedthroughout human alpha-synuclein in Lewy bodies of Parkinson’s disease. JNeurosci Res,2000,59(4):528-533
167.Souza JM, Giasson BI, Chen Q,Lee VM, Ischiropoulos H.Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. implicationof nitrative and oxidative stress in the pathogenesis of neurodegenerativesynucleinopathies. J Biol Chem,2000,275(24):18344-18349
168.Przedborski S,Chen Q,Vila M,Giasson BI,Djaldatti R,et al.Oxidativepost-translational modifications of alpha-synuclein in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’sdisease.J Neurochem,2001,76(2):637-640
169.Schmidt CJ, Matsuda LA, Gibb JW. In vitro release of tritiated monoaminesfromrat CNS tissue by the neurotoxic compound1-methylphenyl-tetrahydropyridine.Eur J Pharmacol,1984,103:255-260
170.Schmidt J, Mertz K, Morgan JI. Regulation of heme oxygenase-1expressionby dopamine in cultured C6glioma and primary astrocytes. Mol Brain Res,1999,73:50-59
171.Marek K, Jennings D, Seibyl J.Do dopamine agonists or levodopa modifyParkinson’s disease progression?.Eur J Neurol.2002, Suppl.3:15-22
172.Whone AL,Watts RL,Stoessl AJ,Davis M,Reske S,Nahmias C,et al. Slowerprogression of Parkinson’s disease with ropinirole vs. levodopa: theREAL-PET study. Ann Neurol,2003,54(1):93-101
173.Fornai F,Battaglia G,Gesi M,Giorqi FS,Orzi F,Nicoletti F,Ruqqieris.Time-course and dose-response study on the effects of chronic l-DOPAadministration on striatal dopamine levels and dopamine transporterfollowing MPTP toxicity. Brain Res,2000,887(1):110-117
174.Melamed E,Offen D,Shirvan A,Ziv I.Levodopa-an exotoxin or a therapeuticdrug?. J Neurol,2000,247(Suppl2):II135-II139
175.D’Amato RJ,Lipman ZP,Snyder SH.Selectivity of the parkinsonianneurotoxin MPTP: toxic metabolite MPP+binds to neuromelanin.Science,1986,231:987-989
176.Jellinger KA.The role of iron in neurodegeneration: prospects forpharmacotherapy of Parkinson’s disease.Drugs Aging,1999,14:115-140
177.Luo L,O’Leary DD. Axon retraction and degeneration in developmentanddisease. Annu Rev Neurosci,2005,28:127-156
178.Low LK,Cheng HJ.A little nip and tuck: axon refinement duringdevelopment and axonal injury. Curr Opin Neurobiol,2005,15,549-556
179.Gunawardena S,Goldstein LS.Cargo-carrying motor vehicles on the neuronalhighway:transport pathways and neurodegenerative disease.J Neurobiol,2004,58:258-271
180.Bito H, Furuyashiki T, Ishihara H, Shibasaki Y,Ohashi K,Mizuno K,et al. Acritical role for a Rhoassociated kinase, p160ROCK, in determining axonoutgrowth in mammalian CNS neurons. Neuron,2000,26(2):431-441
181.Kozma R, Sarner S, Ahmed S, Lim L. Rho family GTPases and neuronalgrowth cone remodelling: relationship between increased complexityinduced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoAand lysophosphatidic acid. Mol Cell Biol,1997,17(3):1201-1211
182.Yamada KM,Spooner BS,Wessells NK.Axon growth:roles of microfilamentsand microtubules. Proc Natl Acad Sci USA,1970,66:1206-1212
183.Baas PW, Qiang L. Neuronal microtubules: when the MAP is the roadblock.Trends Cell Biol,2005,15:183-187
184.King ME, Kan HM, Baas PW, Erisir A,Glabe CG,Bloom GS. Tau-dependentmicrotubule disassembly initiated by prefibrillar {beta}-amyloid. J Cell Biol,2006,175(4);541-546.
185.Qiang L,Yu W,Andreadis A,Luo M,Baas PW. Tau protects microtubules inthe axon from severing by katanin. J Neurosci,2006,26(12):3120-3129
186.Yu W,Solowska JM,Qiang L,Karabay A,Baird D,Bass PW.Regulation ofmicrotubule severing by katanin subunits during neuronal development. JNeurosci,2005,25(23):5573-5583
187.Coleman M. Axon degeneration mechanisms: commonality amid diversity.Nat Rev Neurosci,2005,6;889-898
188.Gillingwater TH, Wishart TM, Chen PE, Haley JE,Robertson K,et al. Theneuroprotective WldS gene regulates expression of PTTG1and erythroiddifferentiation regulator1-like gene in mice and human cells. Hum MolGenet,2006,15(4):625-635
189.Finn JT, Weil M, Archer F,Siman R,Srinivasan A,Raff MC. Evidence thatWallerian degeneration and localized axon degeneration induced by localneurotrophin deprivation do not involve caspases. J Neurosci,2000,20(4):1333-1341
190.Conforti L, Fang G, Beirowski B, Wang MS,Sorci L,Asress S,Adalbert R,etal. NAD(+) and axon degeneration revisited: Nmnat1cannot substitute forWld(S) to delay Wallerian degeneration. Cell Death Differ,2007,14(1):116-127
191.Araki T,Sasaki Y,Milbrandt J.Increased nuclear NAD biosynthesis andSIRT1activation prevent axonal degeneration.Science,2004,305:1010-1013
192.DiAntonio A, Haghighi AP, Portman SL,Lee JD,Amaranto AM,GoodmanCS.Ubiquitination-dependent mechanisms regulate synaptic growth andfunction. Nature,2001,412(6845):449-452
193.Zhai Q,Wang J,KimA,et al. Involvement of the ubiquitin-proteasome systemin the early stages of Wallerian degeneration. Neuron,2003;39:217-225.
194.Hoopfer ED, McLaughlin T,Watts RJ, et al. Wlds protection distinguishesaxon degeneration following injury from naturally occurring developmentalpruning. Neuron,2006;50:883-895.
195.KerschensteinerM, Schwab ME, Lichtman JW, Misgeld T. In vivo imagingof axonal degeneration and regeneration in the injured spinal cord.Nat Med,2005;11:572-577.
196.Awasaki T, Tatsumi R, Takahashi K, et al. Essential role of the apoptotic cellengulfment genes draper and ced-6in programmed axon pruning duringDrosophila metamorphosis.Neuron,2006;50;855-867.
197.MacDonald JM, Beach MG, Porpiglia E, Sheehan AE, Watts RJ, FreemanMR. The Drosophila cell corpse engulfment receptor Draper mediates glialclearance of severed axons. Neuron,2006,50(6):869-881
198.Zhou Z,Hartwieg E,Horvitz HR. CED-1is a transmembrane receptor thatmediates cell corpse engulfment in C elegans. Cell,2001,104:43-56
199.MacInnis BL,Campenot RB.Regulation of Wallerian degeneration and nervegrowth factor withdrawal-induced pruning of axons of sympathetic neuronsby the proteasome and the MEK/Erk pathway. Mol Cell Neurosci,2005,28:430-439
200.Beirowski B,Berek L,Adalbert R,Wagner D,Grumme DS,Addicks K,Ribchester RR,Coleman MP.Quantitative and qualitative analysis ofWallerian degeneration using restricted axonal labelling in YFP-H mice.JNeurosci Methods,2004,134(1):23-35
201.Parson SH, Mackintosh CL, Ribchester RR. Elimination of motor nerveterminals in neonatal mice expressing a gene for slow Walleriandegeneration (C57Bl/Wlds). Eur J Neurosci,1997;9:1586-1592
202.Lee T,Marticke S,Sung C,Robinow S, Luo L.Cell-autonomous requirementof the USP/EcR-B ecdysone receptor for mushroom body neuronalremodeling in Drosophila. Neuron,2000,28(3):807-818.
203.Schubiger M,Wade AA,Carney GE,Truman JW,Bennder M.DrosophilaEcR-B ecdysone receptor isoforms are required for larval molting and forneuron remodeling during metamorphosis.Development,1998,125(11):2053-2062
204.Weimann JM, Zhang YA, Levin ME, Devine WP,Brulet P,McConnell SK.Cortical neurons require Otx1for the refinement of exuberant axonalprojections to subcortical targets. Neuron,1999,24(4):819-831
205.Zhang YA,Okada A,Lew CH,McConnell SK. Regulated nuclear traffickingof the homeodomain protein otx1in cortical neurons. Mol CellNeurosci,2002,19(3):430-446
206.Watts RJ,Hoopfer ED,Luo L.Axon pruning during Drosophilametamorphosis: evidence for local degeneration and requirement of theubiquitin-proteasome system. Neuron,2003,38:871-885
207.MacInnis BL,Campenot RB.Regulation of Wallerian degeneration and nervegrowth factor withdrawal-induced pruning of axons of sympathetic neuronsby the proteasome and the MEK/Erk pathway.Mol Cell Neurosci,2005,28:430-439
208.Kuo CT,Zhu S,Younger S,Jan LY,Jan YN.Identification of E2/E3ubiquitinating enzymes and caspase activity regulating Drosophila sensoryneuron dendrite pruning. Neuron,2006,51(3):283-290
209.Williams DW,Kondo S,Krzyzanowska A,Hiromi Y,Truman JWl.Localcaspase activity directs engulfment of dendrites during pruning.NatNeurosci,2006,9(10):1234-1236
210.Watts RJ,Schuldiner O, Perrino J, Larsen C,Luo L. Glia engulf degeneratingaxons during developmental axon pruning. Curr Biol,2004,14(8):678-684
211.Awasaki T,Ito K. Engulfing action of glial cells is required for programmedaxon pruning during Drosophila metamorphosis. Curr Biol,2004,14:668-677
212.Griffin JW,Georges EB,Hsieh ST,Glass JD.Axonal degeneration anddisorders of the axonal cytoskeleton. In:Waxman SG,Jeffery DK,Stys PK(Eds),The Axon: Structure, Function and Pathophysiology.Oxford UniversityPress, New York, pp.375-390
213.Raff MC,Whitmore AV,Finn JT.Axonal self-destruction and neurodegen-eration. Science,2002,296:868-871
214.Gould TW,Buss RR,Vinsant S,Prevette D,Sun W,Knudson CM,et al.Complete dissociation of motor neuron death from motor dysfunction by Baxdeletion in a mouse model of ALS. J Neurosci,2006,26(34):8774-8786
215.Pun S,Santos AF,Saxena S,Xu L,Caroni P. Selective vulnerability andpruning of phasic motoneuron axons in motoneuron disease alleviated byCNTF. Nat Neurosci,2006,9(3):408-419
216.Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neuronsand their nonneuronal neighbors. Neuron,2006,52:39-59
217.Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; amotor neuron-specific disease. Neuron,2005,48:885-896
218.Gurney ME,Pu H,Chiu AY,Dal Canto MC,Polchow CY,Alexander DD,et al.Motor neuron degeneration in mice that express a human Cu,Zn superoxidedismutase mutation. Science,1994,264(5166):1772-1775
219.Wong RO,Meister M,Shatz CJ.Transient period of correlated burstingactivity during development of the mammalian retina. Neuron,1993,11(5):923-938
220.Collard JF,Cote F,Julien JP.Defective axonal transport in a transgenic mousemodel of amyotrophic lateral sclerosis. Nature,1995,375:61-64
221.Boillee S,Vande Velde C,Cleveland DW. ALS: a disease of motor neuronsand their nonneuronal neighbors. Neuron,2006,55:30-40
222.Lino MM,Schneider C,Caroni P.Accumulation of SOD1mutants in postnatalmotoneurons does not cause motoneuron pathology or motoneuron disease. JNeurosci,2002,22:4825-4832
223.Boillee S,Yamanaka K,Lobsiger CS,Copeland NG,Jenkins NA,KassiotisG,et al.Onset and progression in inherited ALS determined by motor neuronsand microglia. Science,2006,312(5778):1389-1392
224.Fischer LR,Culver DG,Tennant P,Davis AA,Wang M,Castellano-SanchezA,et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence inmice and man. Exp Neurol,2004,185(2):232-240
225.Burke RE.Physiology of motor units. In: Engel, A.G., Franzini-Armstrong, C.(Eds.), Myology. McGraw-Hill, New York,1994, pp:464-484
226.Bommel H,Xie G,Rossoll W,Wiese S,Jablonka S,Boehm T,Sendtner M.Missense mutation in the tubulin-specific chaperone E (Tbce) gene in themouse mutant progressive motor neuronopathy,a model of humanmotoneuron disease. J Cell Biol,2002,159(4):563-569
227.Martin N,Jaubert J,Gounon P,Salido E,Haase G,Szatanik M,Guenet JL.Amissense mutation in Tbce causes progressive motor neuronopathy in mice.Nat Genet,2002,32(3):443-447
228.Sagot Y,Dubois-Dauphin M,Tan SA,de Bilbao F,Aebischer P,MartinouJC,Kato AC. Bcl-2overexpression prevents motoneuron cell body loss butnot axonal degeneration in a mouse model of a neurodegenerative disease. JNeurosci,1995,15(11):7727-7733
229.Hasbani DM,O’Malley KL.Wld(S) mice are protected against the Park-insonian mimetic MPTP. Exp Neurol,2006,202(1):93-99
230.Sajadi A,Schneider BL,Aebischer P. Wlds-mediated protection of dop-aminergic fibers in an animal model of Parkinson disease. Curr Biol,2004,14(4):326-330
231.Fischer LR, Culver DG, Davis AA, Tennant P,Wang M,et al. The WldS genemodestly prolongs survival in the SOD1G93A fALS mouse. Neurobiol Dis,2005,19(1-2):293-300
232.Ferri A,Sanes JR,Coleman MP,Cunningham JM,Kate AC..Inhibiting axondegeneration and synapse loss attenuates apoptosis and disease progressionin a mouse model of motoneuron disease. Curr. Biol,2003,13(8):669-673
233.Stokin GB,Goldstein LS.Axonal transport and Alzheimer’s disease.AnnuRev Biochem,2006,75:607-627
234.Stokin GB,Lillo C,Falzone TL,Brusch RG,Rockenstein E,Mount SL,etal.Axonopathy and transport deficits early in the pathogenesis ofAlzheimer’s disease. Science,2005,307(5713):1282-1288
235.Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronalviability by amyloid precursor protein mutations in Drosophila.Neuron,2001,32:389-401
236.Gunawardena S, Goldstein LS. Polyglutamine diseases and transport prob-lems: deadly traffic jams on neuronal highways.Arch Neurol,2005,62:46-51
237.Eaton BA,Fetter RD,Davis GW.Dynactin is necessary for synapsestabilization. Neuron,2002,34:729-741
238.Garcia-Fresco GP,Sousa AD,Pillai AM,Moy SS,Crawley JN,Tessarollo L, etal. Disruption of axo-glial junctions causes cytoskeletal disorganization anddegeneration of Purkinje neuron axons.Proc Natl Acad Sci USA,2006,103(13):5137-5142
239.Gotz J, Ittner LM, Kins S. Do axonal defects in tau and amyloid precursorprotein transgenic animals model axonopathy in Alzheimer’s disease?. JNeurochem,2006,98(4):993-1006
240.Delio DA, Fiori MG, Lowndes HE. Motor unit function during evolution ofproximal axonal swellings. J Neurol Sci,1992,109(1):30-40
241.Tsai J,Grutzendler J,Duff K,Gan WB.Fibrillar amyloid deposition leads tolocal synaptic abnormalities and breakage of neuronal branches.Nat Neurosci,2004,7(11):1181-1183
242.Mi W,Beirowski B,Gillingwate TH,Adalbert R,Wagner D,Grumme D,et al.The slow Wallerian degeneration gene,WldS,inhibits axonal spheroidpathology in gracile axonal dystrophy mice. Brain,2005,128(pt2):405-416
243.Pirozzi M,Quattrini A,Andolfi G,Dina G,Malaquti MC,Auricchio A,RuqarliEL.Intramuscular viral delivery of paraplegin rescues peripheral axonopathyin a model of hereditary spastic paraplegia.J Clin Invest,2006,116(1):202-208
244.Samsam M, Mi W, Wessig C, Zielasek J, Toyka KV, Coleman MP, MartiniR. The Wlds mutation delays robust loss of motor and sensory axons in agenetic model for myelin-related axonopathy. J Neurosci,2003,23(7):2833-2839
245.Zhang W, Qin LY,Wang TG, et al.32Hydroxymorphinan is neurotrophic todopaminergic neurons and is also neurop rotective against LPS inducedneurotoxicity. FASEB J,2005,19(4):395-397
246.Krieglstein K,Suter-Crazzolara C,Fischer WH and Unsicker K.TGF-βsuperfamily members promote survival of midbrain dopaminergic neuronsand protect them against MPP+toxicity.Eur molec Biol Org,1995,14:736-742
247.Dunnett SB,Bjorklund A.Prospects for new restorative and neuroprotectivetreatments in Parkinson’s disease.Nature,1999,399(6738Suppl):A32-39
248.Schober A.Classic toxin-induced animal models of Parkinson6-OHDA andMPTP.Cell Tissue Res,2004,318(1):215-224
249.Von Bohlen und Halbach O.Modeling neurodegenerative diseases in vivoreview.Neurodegener Dis,2005,2(6):313-320
250.Soderstrom K,O’Malley J,Steece-Collier K,et al.Neural repair strategies forParkinson’s disease:insights from primate models.Cell Transplant,2006,15(3):251-265
251.Cenci MA,Whishaw IQ,Schallert T.Animal models of neurological deficits:how relevant is the rat?.Nat Rev Neurosci,2002,3(7):574-579
252.Schober A.Classic toxin-induced animal models of Parkinson’s disease:6-OHDA and MPTP.Cell Tissue Res,2004,318(1):215-224
253.Schmidt N,Ferger B.Neurochemical findings in the MPTP model ofParkinson’s disease.J Neural Transm,2001,108(11):1263-1282
254.Jackson-Lewis V,Przedborski S.Protocol for the MPTP mouse model ofParkinson’s disease.Nat Protoc,2007,2(1):141-151
255.German DC,Nelson EL,Liang CL,et al.The neurotoxin MPTP causesdegeneration of specific nucleus A8,A9and A10dopaminergic neurons inthe mouse.Neurodegeneration,1996,5(4):229-312
256.Sedelis M,Schwarting RK,Huston JP.Behavioral phenotyping of the MPTPmouse model of Parkinson’s disease.Behav Brain Res,2001,125(1-2):109-125
257.Sundstrom E,Stromberg I,Tsutsumi T,et al.Studies on the effect of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)on central catecholamineneurons in C57BL/6mice.Comparison with three other strains of mice.BrainRes,1987,405(1):26-38
258.Bezard E,Dovero S,Bioulac B,et al.Effects of different schedules of MPTPadministration on dopaminergic neurodegeneration in mice.Exp Neurol,1997,148(1):288-292
259.Tillerson JL,Caudle WM,Reveron ME,et al.Exercise induces behavioralrecovery and attenuates neurochemical deficits in rodent models ofParkinson’s disease.Neuroscience,2003;119(3):899-911
260.Vila M,Vukosavic S,Jackson-Lewis V,et al.Alpha-synuclein up-regulation insubstantia nigra dopaminergic neurons following administration of theparkinsonian toxin MPTP.J Neurochem,2000,74(2):721-729
261.Storch A,Lester HA,Boehm BO,et al.Functional characterization ofdopaminergic neurons derived from rodent mesencephalic progenitor cells.JChem Neuroanat,2003,26(2):133
262.Carrasco E, Werner P.Selective destruction of dopaminergic neurons by lowconcentrations of6-OHDA and MPP+:protection by acetylsalicylic acid(aspirin).Parkinsonism and Related Disorders,2002,8:407-411
263.Yan-Yun Li,Jiang-Hai Lu, Quan Li,et al. Pedicularioside A from Buddleialindleyana inhibits cell death induced by1-methyl-4-phenylpyridinium ions(MPP+) in primary cultures of rat mesencephalic neurons.European Journalof Pharmacology,2008,579:134-140
264.Commissiong JW,Toffano G.The effect of GM-1ganglioside oncoerulospinal,noradrenergic adult neurons and on fetal monoaminerdicneurons transplanted into the transected spinal cord of the adult rat.BrainRes,1986,380:205-214
265.Araki T,Mikami T,Tanji H,Matsubara M,Imai Y,Mizuqaki M,ItoyamaY.Biochemical and immunohistological ehnages in the brain of l-methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP)-terated mouse. Eur J Pharm Sci,2001,12(3):231-238
266.Hofele K,Sedelis M,Aubugrer GW,Morgan S,Huston JP, Schwar rting RK.Evidence for a dissociation between MPTP toxicity and tytrosinase activitybased on congenic mouse strain susceptibility.Exp Neurol,2001,168(1):116-122
267.Seniuk NA,Tatton WG,Greenwood CE.Dose-dependent destruction of thecoeruleus-cortical and nigral-stratal projections by MPTP.Brain Res,1990,527(1):7-20
268.Hartley A,Stone JM,Heron C,Cooper JM,Schapira AH.Complex I inhibitorsinduce dose-dependent apoptosis in PC12cells:relevance to Parkinson’sdisease.J Neurochem,1994,63(5):1987-1990
269.Cochiolo JA,Ehsanian R,Bruck DK. Acute ultrastructural effects of MPTP onthe nigrostriatal pathway of the C57BL/6adult mouse:evidence ofcompensatory plasticity in nigrostriatal neurons.J Neurosci Res,2000,59(1):126-135
270.Gao HM,Hong JS,Zhang W,Liu B.Distinct role for microglia in rotenoneind-uced degeneration of dopaminergic neurons.J Neurosci,2002,22(3):782-790
271.Grammatopoulos TN,Ahmadi F,Jones SM,Fariss MW,Weyhenmeyer JA,Za-wada WM.Angiotensin II protects cultured midbrain dopaminergic neuronsagainst rotenone-induced cell death. Brain Res,2005,1045(1-2):64-71
272.Bruck W.The pathology of multiple sclerosis is the result of focalinflammatory demyelination with axonal damage. J Neurol,2005,252Suppl5:v3-v9
273.Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS:consequences for understanding the progressive phase of the disease. JNeurol Sci,2003,206(2):165-171
274.Brain dopamine and the syndromes of Parkinson and Huntington,Clinical,morphological and neurochemical correlations.J Neurol Sci,1973,20(4):415-455
275.Burns RS,Chiueh CC,Markey SP,Ebert MH,Jacobowitz DM,Kopin IJ.Aprimate model of parkinsonism:selective destruction of dopaminergicneurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Proc Natl Acad Sci USA,1983,80(14):4546-4550
276.Lach B,Grimes D,Benoit B,Minkiewicz-Janda A.Caudate nucleus pathologyin Parkinson's disease:ultrastructural and biochemical findings in biopsymaterial.Acta Neuropathol,1992,83(4):352-360
277.Saxena S,Caroni P. Mechanisms of axon degeneration:From development todisease. Prog Neurobiol,2007,83(3):174-191
278.Fischer LR, Glass JD. Axonal degeneration in motor neuron disease.Neurodegener Dis,2007,4(6):431-442
279.Sherriff FE,Bridges LR,Sivaloganathan S. Early Detection of Axonal Injuryafter Human Head Trauma using Immunocytochemist ry for Beta-amyloidPrecursor Protein. Acta Neuropathol (S0001-6322),1994;87(1):55-62
280.Blumbergs PC, Scott G, Manavis J,Wainwright H,Simpson DA,Mclean A.Topography of axonal injury as defined by amyloid precursor protein and thesector scoring method in mild and severe closed head injury. J Neurotrauma,1995,12(4):565-572
281.Stone JR, Singleton RH, Povlishock JT. Antibodies to the Cterminus of thebeta-amyloid precursor protein (APP): a site specific marker for the detectionof traumatic axonal injury. Brain Res,2000,871(2):288-302
282.刘洪恩,孙晓川. β-淀粉样前体蛋白与弥漫性轴索损伤.创伤外科杂志,2005,7(1):73-75
283.Loers G, Aboul-Enein F, Bartsch U,Lassmann H,Schcahner M. Comparisonof myelin, axon, lipid, and immunopathology in the central nervous systemof differentially myelin-compromised mutant mice: a morphological andbiochemical study. Mol Cell Neurosci,2004,27(2):175-189
284.Nogales E. Structural insights into microtubule function. Annu Rev Biochem,2000,69:277-302
285.Ren Y, Zhao J, Feng J. Parkin binds to alpha/beta tubulin and increases theirubiquitination and degradation. J Neurosci,2003,23(8):3316-3324
286.Feng J. Microtubule:a common target for parkin and parkinson’s diseasetoxins. Neuroscientist,2006,12(6):469-476
287.Cappelletti G,Pedrotti B,Maggioni MG,Maci R..Microtubule assembly isdirectly affected by MPP+in vitro.Cell Biol Int,2001,25(10):981-984
288.Cappelletti G, Surrey T, Maci R. The parkinsonism producing neurotoxinMPP+affects microtubule dynamics by acting as a destabilising factor. FEBSLett,2005,579(21):4781-4786
289.Coleman M. Axon degeneration mechanisms: commonality amid diversity.Nature reviews,Neuroscience.2005,6(11):889-898
290.Mimura F,Yamagishi S,Arimura N,Fujitani M,Kubo T,KaibuchiK,Yamasgita T.Myelin-associated glycoprotein inhibits microtubuleassembly by a Rho-kinase-dependent mechanism.J Biol Chem,2006,281(23):15970-15979
291.Uchida Y, Ohshima T, Sasaki Y, Suzuki S,Yamashita N,Nakamuta F,et al.Semaphorin3A signalling is mediated via sequential Cdk5and GSK3betaphosphorylation of CRMP2: implication of common phosphorylatingmechanism underlying axon guidance and Alzheimer's disease. Genes cells,2005,10(2):165-179
292.Youdim MB, Arraf Z. Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium:involvements of Bcl-2and Bax. Neuropharmacology,2004;46(8):1130-1140.
293.Xu J, Culman J, Blume A, Brecht S, Gohlke P. Chronic treatment with a lowdose of lithium protects the brain against schemic injury by reducingapoptotic death. Stroke,2003;34(5):1287-92.
294.Fujimura M, Usuki F, Kawamura M, Izumo S. Inhibition of the Rho/ROCKpathway prevents neuronal degeneration in vitro and in vivo followingmethylmercury exposure. Toxicol Appl Pharmacol,2011;250(1):1-9.
295.Manji HK, Chen G. PKC, MAP kinases and the bcl-2family of proteins aslong-term targets for mood stabilizers. Mol Psychiatry,2002;7Suppl1:S46-S56.
296.Manji HK, Moore GJ, Chen G. Lithium at50: have the neuroprotectiveeffects of this unique cation been overlooked?.Biol Psychiatry,1999;46(7):929-940.
297.Nonaka S, Chuang DM. Neuroprotective effects of chronic lithium on focalcerebral ischemia in rats. Neuroreport,1998;9(9):2081-2084.
298.Chen G, Zeng WZ, Yuan PX, Huang LD,Jiang YM,Zhao ZH,Manji HK. Themood-stabilizing agents lithium and valproate robustly increase the levelsofthe neuroprotective protein bcl-2in the CNS. J Neurochem,1999;72(2):879-882.
299.Chen RW, Chuang DM. Long term lithium treatment suppresses p53andBax expression but increases Bcl-2expression:A prominent role in neuro-protection against excitotoxicity. J Biol Chem,1999;274(10):6039-6042.
300.Chalecka-Franaszek E, Chuang DM. Lithium activates the serine/threoninekinase Akt-1and suppresses glutamate-induced inhibition of Akt-1activityin neurons. Proc Natl Acad Sci USA,1999:96(15):8745-8750.
301.Martin L,Magnaudeix A,Esclaire F,Yardin C,Terro F.Inhibition of glycogensynthase kinase-3β down regulates total tau proteins in cultured neurons andits reversal by the blockade of preotein phosphatase-2α.Brain Res,2009;1252:66-75
302.Goverk EE,Newey SE,Van Aelst L.The role of the Rho GTPases in neuronaldevelopment.Genes Dev,2005,19(1):1-49
303.Sasaki Y, Suzuki M, Hidaka H. The novel and specific Rho-kinaseinhibitor(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol.Ther,2002;93(2-3):225-232.
304.Mukai H. The structure and function of PKN, a protein kinase having acatalytic domain homologous to that of PKC.J Biochem,2003;133(1):17-27.
305.Janeczek AH,Van Alten PJ,Reyes HM,Walter RJ.Modulation of thecytoskeleton and intracellular calcium in leukocyte exhibiting acancer-associated chemotaxis defect. J Leukoc Biol,1993;54(4):351-359.