帕金森病的脑深部电刺激治疗与脑脊液蛋白变化的相关性研究
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摘要
背景:帕金森病(Parkinson's disease,PD)是最常见的老年性神经疾病之一,其主要临床特征是静止性震颤、肌强直、运动减少和姿势平衡障碍等。PD的病因目前仍不十分清楚。研究认为PD黑质中多巴胺能神经元的变性坏死与蛋白的异常聚集有关。目前PD的诊断主要依据临床表现,尚无特异性的生物标志物用于诊断和鉴别诊断。因而,PD相关蛋白的研究是近几年的热点之一。但是,在CSF中研究PD相关蛋白的报道罕见,在国内尚未见相关报道。
作为外科治疗手段之一的慢性脑深部电刺激(DBS)由于其安全、有效、可调和可逆等优点于1987年以来被广泛用于PD的临床治疗。但是其治疗的机制却不清楚。现在已经知道蛋白质在PD发病机制中起着重要的作用,而DBS应用后是否对脑脊液蛋白产生影响,目前国内外还没有文献报道。
目的:本研究拟采用蛋白质组学技术对PD患者脑脊液中蛋白质进行研究,建立蛋白表达谱,了解PD相关蛋白的表达情况,找出PD与正常对照组存在的差异蛋白点以尽可能地发现关键性蛋白,以期对PD的发病机制及诊断提供可能线索和生物标志物;以及通过测定手术损伤后和DBS治疗后脑脊液中各种相关蛋白的变化,以探讨DBS治疗的作用机制;同时通过综合评价DBS治疗前后脑脊液各种相关蛋白的变化与统一帕金森病评定量表(unified Parkinson's disease rating scale,UPDRS)中运动评分及日常生活能力(activities of daily living,ADL)评分之间的相关性,为DBS疗效的判定提供理论依据和可能的生物学检测指标。
方法:本研究收集9例PD患者、8例正常对照者、5例DBS治疗者的脑脊液,采用荧光差异凝胶电泳(DIGE)技术分离并筛选PD和正常对照者以及DBS前后脑脊液中差异表达蛋白质,用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF/MALDI-TOF-TOF)和电喷雾串联质谱(ESI-MS-MS)技术结合蛋白质数据库对这些差异蛋白质进行鉴定并分析。使用免疫印迹(Western-blot)技术对部分鉴定的蛋白质进行验证。分别在药物“开”和“关”的状态下,术前第一天和开机后第7天对5名DBS治疗者进行统一帕金森病评定量表(UPDRS)中的第Ⅱ部分日常生活能力和第Ⅲ部分运动能力进行评分,分别进行统计学处理同时计算其改善率。
结果:5名DBS患者在手术中均出现“微毁损效应”,所有患者DBS后症状改善明显,无论在药物“开”还是“关”状态,其运动评分及日常生活能力评分均显著改善。DIGE方法显示匹配点相对比值选择为＞1.5倍或＜-1.5倍时,PD和正常对照间有20个明显的差异蛋白点,其中11个点在PD中上调,9个点下调;匹配点相对比值选择＞1.2倍或＜-1.2倍时,PD和正常对照间有48个明显差异蛋白点,其中19个蛋白点发生下调,29个蛋白点发生上调。MALDI-TOF/MALDI-TOF-TOF和ESI-MS-MS共鉴定出21个蛋白质,其中3个蛋白为白蛋白的异构体(片段?),5个蛋白为免疫球蛋白的片断,2个蛋白为apoA-I异构体,3个蛋白为未知蛋白,13个蛋白属于潜在的PD相关蛋白。其中蛋白MYPT1首次发现在CSF中表达。蛋白apoA-I、MYPT1、tetranectin、C4A首次被发现与PD有潜在相关性。用Western-blot方法验证了apoA-I、MYPT1、C4、IgA、tetranectin、EC-SOD等6个蛋白,发现MYPT1无法测出,其余5个蛋白用Western-blot方法在PD患者和正常对照者CSF中均测出有明确表达,而且在正常对照者和PD患者中的表达与DIGE方法所测均基本一致。但在DBS前后CSF中的表达与DIGE方法所测略有出入。
结论:在13个属于PD潜在的相关蛋白中,部分蛋白有可能成为PD的生物标记物。而部分DBS前后改变明显的蛋白,有可能成为监测DBS疗效的生物学指标。DBS治疗的机制之一可能是通过与毁损不完全相同的机制维持或进一步促进微毁损的治疗效果。
Background:Parkinson's disease(PD) is one of the common neurodegenerative disorders characterized by a progressive loss of dopaminergic neurons in the substantia nigra,striatum and putamen,resulting in extrapyramidal motor dysfunction, including resting tremor,rigidity,bradykinesia and postural instability.The pathogenesis of PD is not yet clear.Increasing evidence has suggested that degeneration and loss of dopaminergic neurons in the substantia nigra have links with abnormal protein aggregation.The clinical diagnosis of PD is based entirely on clinical features.There is no special biomarker for PD in diagnosis and differential diagnosis.PD related proteins are becoming research hotspot in recent years. However,the reports on PD related proteins in cerebrospinal fluid(CSF) to date are rare,and there is no report yet on this field in China.
As one of the surgical method for PD therapy,deep brain stimulation(DBS) is safe,effective,adaptable,and reversible,and increasingly being used across the world since 1987.However,its primary mechanisms of action are yet poorly understood.It has been known that proteins play important roles in pathological processes of PD.Up to now,there is still no research to report whether DBS has effects on proteins in CSF.
Objectives:To compare protein profiles in the CSF between PD patients and control subjects and to identify the PD-related proteins that might serve as potential biomarkers or clues for diagnosis or pathogenesis.Moreover,to quantitate the variation of protein expression in CSF pre-DBS and post-DBS to explore the mechanisms of DBS for the treatment of PD.Evaluating possible relations between the variations of protein expressions in CSF pre- and post-DBS and the Unified Parkinson's Disease Rating Scale(UPDRS) motor scores and activities of daily living (ADL) scores to find out potential biological markers for monitoring the efficacy of DBS.
Methods:The CSF from 9 PD patients,8 control subjects,and 5 DBS patents was studied for the differentially expressed proteins in patients with PD compared with controls,in pre-DBS patients compared with post-DBS by two-dimensional difference gel electrophoresis(2D DIGE) technique,in combination with matrix-assisted laser desorption/ ionization- time of flight(MALDI-TOF) and tandem(TOF-TOF) mass spectrometry or electrospray ionization tandem mass spectrometry(ESI-MS- MS). Western-blotting was used to validate the data of proteomic analysis.The motor scores and ADL scores of UPDRS for 5 DBS patients were valuated on the day before operation and the 7~(th) day after chronic stimulation starting(stimulator on) in state of ON medication and OFF medication respectively.Statistic analysis on UPDRS scores were performed for improvement.
Results:Micro-lesioning effects were observed during operation in all 5 patients with PD.The scores of motor and ADL were significantly improved after DBS in both on-medication and off-medication condition.DIGE analysis showed that the levels of 20 protein spots were significantly altered in PD CSF when average ratio of the matched spot was assigned as＞1.5 or＜-1.5.Of which,11 spots were up-regulated and 9 spots were down-regulated.48 spots were significantly altered in PD patients compared with controls when average ratio＞1.2 or＜-1.2.Of which 19 spots were considerably down-regulated in the CSF of PD patients,whereas 29 spots were considerably up-regulated.21 unique proteins(including redundancies due to proteolysis and post-translationally modified isoforms) were identified after MS and protein database interrogation.Of them 3 were albumin isoforms(fragments ?),5 were fragments of immune globin,2 were apolipoproteinA-Ⅰ(apo A-Ⅰ) isoforms,3 were unnamed proteins.13 of 21 proteins were potentially PD-related proteins. Myosin phosphatase target subunit 1(MYPT1) was identified for the first time in CSF, and apoA-Ⅰ,MYPT1,tetranectin,C4A were identified for the first time in the CSF of PD patients.The expression levels of C4,apoA-Ⅰ,IgA,tetranectin,extracellular superoxide dismutase(EC-SOD),detected by Western-blotting,correlated well with the DIGE results in PD patients and controls,and differed partially from the DIGE results in pre- and post-DBS patients.
Conclusions:some of 13 proteins which belonged to potential PD related protein may serve as possible biomarkers for PD,and some of the proteins altered significantly pre- and post-DBS may be useful for better understanding of mechansism of DBS. The role of DBS for PD is probably to sustain or promote effects of micro-lesioning by the mechanism different from lesioning.
作为外科治疗手段之一的慢性脑深部电刺激(DBS)由于其安全、有效、可调和可逆等优点于1987年以来被广泛用于PD的临床治疗。但是其治疗的机制却不清楚。现在已经知道蛋白质在PD发病机制中起着重要的作用,而DBS应用后是否对脑脊液蛋白产生影响,目前国内外还没有文献报道。
目的:本研究拟采用蛋白质组学技术对PD患者脑脊液中蛋白质进行研究,建立蛋白表达谱,了解PD相关蛋白的表达情况,找出PD与正常对照组存在的差异蛋白点以尽可能地发现关键性蛋白,以期对PD的发病机制及诊断提供可能线索和生物标志物;以及通过测定手术损伤后和DBS治疗后脑脊液中各种相关蛋白的变化,以探讨DBS治疗的作用机制;同时通过综合评价DBS治疗前后脑脊液各种相关蛋白的变化与统一帕金森病评定量表(unified Parkinson's disease rating scale,UPDRS)中运动评分及日常生活能力(activities of daily living,ADL)评分之间的相关性,为DBS疗效的判定提供理论依据和可能的生物学检测指标。
方法:本研究收集9例PD患者、8例正常对照者、5例DBS治疗者的脑脊液,采用荧光差异凝胶电泳(DIGE)技术分离并筛选PD和正常对照者以及DBS前后脑脊液中差异表达蛋白质,用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF/MALDI-TOF-TOF)和电喷雾串联质谱(ESI-MS-MS)技术结合蛋白质数据库对这些差异蛋白质进行鉴定并分析。使用免疫印迹(Western-blot)技术对部分鉴定的蛋白质进行验证。分别在药物“开”和“关”的状态下,术前第一天和开机后第7天对5名DBS治疗者进行统一帕金森病评定量表(UPDRS)中的第Ⅱ部分日常生活能力和第Ⅲ部分运动能力进行评分,分别进行统计学处理同时计算其改善率。
结果:5名DBS患者在手术中均出现“微毁损效应”,所有患者DBS后症状改善明显,无论在药物“开”还是“关”状态,其运动评分及日常生活能力评分均显著改善。DIGE方法显示匹配点相对比值选择为＞1.5倍或＜-1.5倍时,PD和正常对照间有20个明显的差异蛋白点,其中11个点在PD中上调,9个点下调;匹配点相对比值选择＞1.2倍或＜-1.2倍时,PD和正常对照间有48个明显差异蛋白点,其中19个蛋白点发生下调,29个蛋白点发生上调。MALDI-TOF/MALDI-TOF-TOF和ESI-MS-MS共鉴定出21个蛋白质,其中3个蛋白为白蛋白的异构体(片段?),5个蛋白为免疫球蛋白的片断,2个蛋白为apoA-I异构体,3个蛋白为未知蛋白,13个蛋白属于潜在的PD相关蛋白。其中蛋白MYPT1首次发现在CSF中表达。蛋白apoA-I、MYPT1、tetranectin、C4A首次被发现与PD有潜在相关性。用Western-blot方法验证了apoA-I、MYPT1、C4、IgA、tetranectin、EC-SOD等6个蛋白,发现MYPT1无法测出,其余5个蛋白用Western-blot方法在PD患者和正常对照者CSF中均测出有明确表达,而且在正常对照者和PD患者中的表达与DIGE方法所测均基本一致。但在DBS前后CSF中的表达与DIGE方法所测略有出入。
结论:在13个属于PD潜在的相关蛋白中,部分蛋白有可能成为PD的生物标记物。而部分DBS前后改变明显的蛋白,有可能成为监测DBS疗效的生物学指标。DBS治疗的机制之一可能是通过与毁损不完全相同的机制维持或进一步促进微毁损的治疗效果。
Background:Parkinson's disease(PD) is one of the common neurodegenerative disorders characterized by a progressive loss of dopaminergic neurons in the substantia nigra,striatum and putamen,resulting in extrapyramidal motor dysfunction, including resting tremor,rigidity,bradykinesia and postural instability.The pathogenesis of PD is not yet clear.Increasing evidence has suggested that degeneration and loss of dopaminergic neurons in the substantia nigra have links with abnormal protein aggregation.The clinical diagnosis of PD is based entirely on clinical features.There is no special biomarker for PD in diagnosis and differential diagnosis.PD related proteins are becoming research hotspot in recent years. However,the reports on PD related proteins in cerebrospinal fluid(CSF) to date are rare,and there is no report yet on this field in China.
As one of the surgical method for PD therapy,deep brain stimulation(DBS) is safe,effective,adaptable,and reversible,and increasingly being used across the world since 1987.However,its primary mechanisms of action are yet poorly understood.It has been known that proteins play important roles in pathological processes of PD.Up to now,there is still no research to report whether DBS has effects on proteins in CSF.
Objectives:To compare protein profiles in the CSF between PD patients and control subjects and to identify the PD-related proteins that might serve as potential biomarkers or clues for diagnosis or pathogenesis.Moreover,to quantitate the variation of protein expression in CSF pre-DBS and post-DBS to explore the mechanisms of DBS for the treatment of PD.Evaluating possible relations between the variations of protein expressions in CSF pre- and post-DBS and the Unified Parkinson's Disease Rating Scale(UPDRS) motor scores and activities of daily living (ADL) scores to find out potential biological markers for monitoring the efficacy of DBS.
Methods:The CSF from 9 PD patients,8 control subjects,and 5 DBS patents was studied for the differentially expressed proteins in patients with PD compared with controls,in pre-DBS patients compared with post-DBS by two-dimensional difference gel electrophoresis(2D DIGE) technique,in combination with matrix-assisted laser desorption/ ionization- time of flight(MALDI-TOF) and tandem(TOF-TOF) mass spectrometry or electrospray ionization tandem mass spectrometry(ESI-MS- MS). Western-blotting was used to validate the data of proteomic analysis.The motor scores and ADL scores of UPDRS for 5 DBS patients were valuated on the day before operation and the 7~(th) day after chronic stimulation starting(stimulator on) in state of ON medication and OFF medication respectively.Statistic analysis on UPDRS scores were performed for improvement.
Results:Micro-lesioning effects were observed during operation in all 5 patients with PD.The scores of motor and ADL were significantly improved after DBS in both on-medication and off-medication condition.DIGE analysis showed that the levels of 20 protein spots were significantly altered in PD CSF when average ratio of the matched spot was assigned as＞1.5 or＜-1.5.Of which,11 spots were up-regulated and 9 spots were down-regulated.48 spots were significantly altered in PD patients compared with controls when average ratio＞1.2 or＜-1.2.Of which 19 spots were considerably down-regulated in the CSF of PD patients,whereas 29 spots were considerably up-regulated.21 unique proteins(including redundancies due to proteolysis and post-translationally modified isoforms) were identified after MS and protein database interrogation.Of them 3 were albumin isoforms(fragments ?),5 were fragments of immune globin,2 were apolipoproteinA-Ⅰ(apo A-Ⅰ) isoforms,3 were unnamed proteins.13 of 21 proteins were potentially PD-related proteins. Myosin phosphatase target subunit 1(MYPT1) was identified for the first time in CSF, and apoA-Ⅰ,MYPT1,tetranectin,C4A were identified for the first time in the CSF of PD patients.The expression levels of C4,apoA-Ⅰ,IgA,tetranectin,extracellular superoxide dismutase(EC-SOD),detected by Western-blotting,correlated well with the DIGE results in PD patients and controls,and differed partially from the DIGE results in pre- and post-DBS patients.
Conclusions:some of 13 proteins which belonged to potential PD related protein may serve as possible biomarkers for PD,and some of the proteins altered significantly pre- and post-DBS may be useful for better understanding of mechansism of DBS. The role of DBS for PD is probably to sustain or promote effects of micro-lesioning by the mechanism different from lesioning.
引文
1. Klunk W.E.. Blood and CSF biomarkers for AD revisited: what's new, what's good, and is this where we should be looking? Neurobiology of Aging, 2002, 23 :517-519
2. Khachaturian Z.S. The challenges of developing and validating molecular and biochemical markers of Alzheimer's disease . Neurobiology of Aging , 2002, 23 :509-511
3. Pia Davidsson , Magnus Sjogren. The use of proteomics in biomarker discovery in neurodegenerative diseases. Disease Markers, 2005, 21: 81-92
4. Unlu M., Morgan M. E., and Minden J. S. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis, 1997, 18:2071-2077
5. Tonge R., Shaw J., Middleton B., et al. Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology. Proteomics, 2001,1:377-396
6. Richard E., Monteoliva L., Juarez S.,et al. Quantitative Analysis of Mitochondrial Protein Expression in Methylmalonic Acidemia by Two-Dimensional Difference Gel Electrophoresis. Journal of Proteome Research, 2006, 5:1602-1610
7. Nakano T., Ito M., Tanaka J., et al. Localization of the gene coding for myosin phosphatase, target subunit 1 (MYPT1) to human chromosome 12q15-q21. Genomics, 1997,44:150-152
8. Ito M. , Nakano T., Erdodi F.,et al. Myosin phosphatase: Structure, regulation and function. Molecular and Cellular Biochemistry, 2004, 259: 197-209
9. Lontay B, Serfozo Z , Gergely P, et al .Localization of Myosin Phosphatase Target Subunit 1 in Rat Brain and in Primary Cultures of Neuronal Cells. J Comp Neurol, 2004,478 (1) :72-87
10. Wu Y., Muranyi A., Erdodi F. et al. Localization of myosin phosphatase target subunit and its mutants. Journal of Muscle Research and Cell Motility , 2005,26:123-134
11. Wishart T. M, Parson S.H., and Gillingwater T. H. Synaptic Vulnerability in Neurodegenerative Disease. J Neuropathol Exp Neurol, 2006, 65(8): 733-739
12. Mukaetova-Ladinska E.B., McKeith I.G. Pathophysiology of synuclein aggregation in Lewy body disease. Mechanisms of Ageing and Development, 2006, 127:188-202
13.Suehiro T.,Yamamoto M.,Yoshida K.Increase of Plasma Proapolipoprotein A-I in Patients with Liver Cirrhosis and Its Relationship to Circulating High-Density Lipoproteins 2 and 3.Clinical Chemistry,1993,39(1):60-65
14.Ghiselli G,Gotto AM Jr,Tanenbaum S,et al.Proapolipoprotein A-I conversion kinetics in vivo in human and in rat.Proc.Natl.Acad.Sci.USA,1985,82(3):874-878
15.Chan D.C.and Watts G.F..Apolipoproteins as markers and managers of coronary risk.Q J Med,2006;99:277-287
16.Davidsson P.,Westman-Brinkmalm A.,Nilsson C.L.Proteome analysis of cerebrospinal fluid proteins in Alzheimer patients.NeuroReport,2002,13:611-615
17.Gursky O..Apolipoprotein structure and dynamics.Current Opinion in Lipidology,2005,16:287-294
18.Sorci-Thomas M.G.,Thomas M.J.The effects of altered apolipoprotein A-I structure on plasma HDL concentration.Trends Cardiovasc Med,2002,12:121-128.
19.Lotharius J.and Brundin P.Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.Human Molecular Genetics,2002,11(20):2395-2407
20.Song H,Saito K,Seishima M.,et al.Cerebrospinal fluid apoE and apoA-I concentrations in early- and late-onset Alzheimer's disease.Neurosci Lett,1997,231:175-178
21.Merched A,Xia Y,Visvikis S.,et al.Dereased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease.Neurobiol Aging,2000,21:27-30
1.Kim S.I.,Voshol H.,van Oostrum J.,et al.Neuroproteomics:expression profiling of the brain's proteomes in health and disease.Neurochem Res,2004,29(6):1317-1331
2.Hague S.M.,Klaffke S.,Bandmann O..Neurodegenerative disorders:Parkinson's disease and Huntington's disease.J Neurol Neurosurg Psychiatry,2005,76:1058-1063
3.Iuliis A.D.,Grigoletto J.,Recchia A.,et al.A proteomic approach in the study of an animal model of Parkinson's disease.Clinica Chimica Acta,2005,357:202-209
4.Volkmann J.Deep Brain Stimulation for the Treatment of Parkinson's Disease.J Clin Neurophysiol,2004;21:6-17
5.Walter BL,Vitek JL.Surgical treatment for Parkinson's disease.Lancet Neurol, 2004.3:719-728
6.杨晨,江澄川.脑深部刺激治疗帕金森病的疗效回顾.中华神经外科杂志,2006,22(5):319-321
7.姜秀峰,周晓平,胡小吾等.丘脑底核脑深部刺激术的参数设置及调整.中国微侵袭神经外科杂志.2006,11(3):105-107
8.McIntyre C.C.,Savasta M.,Walter B.L.,et al.How Does Deep Brain Stimulation Work? Present Understanding and Future Questions.J Clin Neurophysiol,2004;21:40-50
9.Hashimoto T,Elder CM,Okun MS,et al.Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons.J Neurosci,2003,23:1916-1923.
10.Jech R,Urgosik D,Tintera J,et al.Functional magnetic resonance imaging during deep brain stimulation:a pilot study in four patients with Parkinson's disease.Mov Disord,2001,16:1126-1132.
11.Jech R.Effects of deep brain stimulation of the STN and Vim nuclei under resting state and during simple movement task.A functional MRI study at 1.5 Tesla.Mov Disord,2002,17:S173.
12.Haslinger B,Boecker H,Buchel C,et al.Differential modulation of subcortical target and cortex during deep brain stimulation.Neuroimage,2003,18:517-524.
13.Goldfarb R.D.,Parrillo J.E..Complement.Crit Care Med,2005,33(12(Suppl.)):s482-s484
14.Reilly B.D..Structural comparison of human C4A3 and C4B1 after proteolytic activation by C1s.Molecular Immunology,2006,43:800-811
15.Law,S.K.A.,Dodds,A.W.,Porter,R.R..A comparison of the properties of two classes,C4A and C4B,of the human complement component C4.EMBO J,1984,3:1819-1823
16.Kasuya,H.Shimizu,T.Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage.Journal of Neurosurgery,1989,71(5 Pt 1):741-746
17.Michele Mussap and Mario Plebani.Biochemistry and Clinical Role of Human Cystatin C.Critical Reviews in Clinical Laboratory Sciences,2004,41(5-6):467-550
18.Merz GS,Benedikz E,Schwenk V,et al.Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells.J Cell Physiol,1997,173:423-32.
19. Bjamadottir M, Nilsson C, Lindstrom V, et al. The cerebral hemorrhage-producing cystatin C variant (L68Q) in extracellular fluids. Amyloid, 2001; 8: 1-10.
20. Ognibene A., Mannucci E., Caldini A., et al. Cystatin C reference values and aging. Clinical Biochemistry, 2006, 39:658-661
21. Brettschneider J., Riepe M.W., Petereit H.F.,et al. Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus? J Neurol Neurosurg Psychiatry, 2004. 75:1614-1616
22. Ruetschi U., Zetterberg H., Podust V. N., et al. Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF . Experimental Neurology, 2005, 196:273-281
23. Pasinetti G.M., Ungar L.H., Lange D.J., et al. Identification of potential CSF biomarkers in ALS. Neurology, 2006, 66:1218-1222
24. Carrette, O., Demalte, I., Scherl, A., et al. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics, 2003, 3:1486-1494.
25. Ghidoni R., Benussi L., Paterlini A., et al. Presenilin 2 mutations alter cystatin C trafficking in mouse primary neurons. Neurobiology of Aging , 2007, 28: 371-376
26. Natasa Kopitar-Jerala . The role of cystatins in cells of the immune system. FEBS Letters, 2006,580:6295-6301
27. Palm D. E., Knuckey N.W., Primiano M.J., et al. Cystatin C, a protease inhibitor, in degenerating rat hippocampal neurons following transient forebrain ischemia. Brain Research, 1995, 691: 1 -8
28. Deng A., Irizarry M.C., Nitsch R.M., et al. Elevation of cystatin C in susceptible neurons in Alzheimer's disease. Am J Pathol, 2001, 159: 1061-1068.
29. Ying G.-X., Huang C, Jiang Z.-H., et al. Up-regulation of cystatin C expression in the murine hippocampus following perforant path transaction . Neuroscience , 2002;112(2):289-298
30. Xu L., Sheng J.-S., Tang Z.-S, et al. Cystatin C prevents degeneration of rat nigral dopaminergic neurons: in vitro and in vivo studies. Neurobiology of Disease , 2005,18: 152-165
31. Pirttila T. J., Lukasiuk K., Hakansson K., et al.Cystatin C modulates neurodegeneration and neurogenesis following status epilepticus in mouse. Neurobiology of Disease, 2005.20 : 241-253
32. Nishiyama K., Konishi A., Nishio C, et al. Expression of cystatin C prevents oxidative stress-induced death in PC12 cells. Brain Research Bulletin, 2005, 67: 94-99
33. Levy E., Sastre M., Kumar A., et al. Codeposition of cystatin C with amyloid-beta protein in the brain of Alzheimer disease patients, J Neuropathol Exp Neurol, 2001,60:94-104.
34. Nagai A., Ryu J. K., Terashima M.., et al. Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B . Brain Research , 2005, 1066:120 - 128
35. Holtet TL, Graversen JH, Clemmensen I, et al. Tetranectin, a trimeric plasminogen-binding C type lectin. Protein Sci, 1997, 6:1511-1515.
36. Obrist P., Spizzo G, Ensinger C, et al. Aberrant tetranectin expression in human breast carcinomas as a predictor of survival. J Clin Pathol, 2004,57:417-421.
37. Wewer U.M. , Iba K. , Durkin M. E., et al. Tetranectin is a novel marker for myogenesis during embryonic development, muscle regeneration, and muscle cell differentiation in vitro. Dev Biol, 1998, 200: 247-259
38. Wewer UM, Ibaraki K, Schjorring P, et al. A potential role for tetranectin in mineralization during osteogenesis. J Cell Biol, 1994, 127:1767 - 1775.
39. Hogdall C.K. , Christiansen M, Norgaard-Pedersen B., et al. Plasma Tetranectin and Colorectal Cancer . European journal of Cancer ,1995, 31A (6): 888-894
40. Obrist P., Spizzo G, Ensinger C, et al. Aberrant tetranectin expression in human breast carcinomas as a predictor of survival. J Clin Pathol, 2004, 57:417-421.
41. Hammack BN, Fung KY, Hunsucker SW, et al. Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult Scler, 2004,10:245- 260.
42. Stoevring B., Jaliashvili I., Thougaard A.V., et al. Tetranectin in cerebrospinal fluid: Biochemical characterisation and evidence of intrathecal synthesis or selective uptake into CSF. Clinica Chimica Acta , 2005, 359: 65-71
43. Liu X.D., Zeng B.-F., Xu J.-G, et al. Proteomic analysis of the cerebrospinal fluid of patients with lumbar disk herniation. Proteomics, 2006, 6:1019-1028
44. Dietzmann, K., von Bossanyi P., Krause, D., et al. Expression of the plasminogen activator system and the inhibitors PAI-1 and PAI-2 in posttraumatic lesions of the CNS and brain injuries following dramatic circulatory arrests: an immunohistochemical study. Pathol Res Pract, 2000. 196 (1): 15-21
45. Zelko I.N., Mariani T. J., and Folz R. J. . Superoxide Dismutase Multigene Family: A Comparison of The CuZn-SOD (SOD1), Mn-SOD (SOD2), And EC-SOD (SOD3) Gene Structures, Evolution, And Expression. Free Radical Biology & Medicine, 2002, 33(3):337-349
46. Fattman C. L., Schaefer L. M, and Oury T.. Extracellular superoxide dismutase in biology and medicine. Free Radical Biology & Medicine, 2003, 35(3): 236-256
47. FolzR. J. , Guan J., Seldin M. F., et al. Mouse Extracellular Superoxide Dismutase: Primary Structure, Tissue-specific Gene Expression, Chromosomal Localization,and Lung In Situ Hybridization. Am J Respir Cell Mol Biol, 1997, 17:393-403.
48. Nakane H., Chu Y., Faraci F. M.,et al. Gene Transfer of Extracellular Superoxide Dismutase Increases Superoxide Dismutase Activity in Cerebrospinal Fluid. Stroke, 2001, 32:184-189
49. Oury T.D., Card J.P.,Klann, E. Localization of extracellular superoxide dismutase in adult mouse brain. Brain Res, 1999, 850:96-103
50. Rola R., Zou Y., Huang T-T, et al. Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radical Biology & Medicine, 2007,42:1133-1145
51. Sheng H., Bart R.D., Oury T.D., et al. Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience, 1999, 88:185-191
52. Hu D., Serrano F., Oury T.D., et al. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J Neurosci, 2006, 26: 3933- 3941
53. Watanabe Y, Chu Y, Andresen J. J., et al. Gene Transfer of Extracellular Superoxide Dismutase Reduces Cerebral Vasospasm After Subarachnoid Hemorrhage. Stroke, 2003, 34:434-440
54. Yamaguchi M., Zhou C, Heistad D. D., et al. Gene Transfer of Extracellular Superoxide Dismutase Failed to Prevent Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage. Stroke, 2004, 35:2512-2517
55. van Egmond M., Damen C.A., van Spriel A. B., et al. IgA and the IgA Fc receptor . TRENDS in Immunology , 2001, 22 (4): 205-211
56. Yoo E.M., Morrison S. L. IgA: An immune glycoprotein. Clinical Immunology, 2005, 116:3-10
57. Deisenhammer F., Bartos A., Egg R., et al. Guidelines on routine cerebrospinal fluid analysis.Report from an EFNS task Force.European Journal of Neurology,2006,13:913-922
58.Sobek O.,Adam P.On S.Seygert,V.Kunzmann,N.Schwertfeger,H.C.Koch,A.Faulstich:Determinants of lumbar CSF protein concentration.J Neurol,2003,250:371-372
59.Leary S.M.,McLean B.N.,Thompson E.J.Local synthesis of IgA in the cerebrospinal fluid of patients with neurological diseases.J Neurol,2000,247:609-615
60.Reiber H.,Peter J.B.Cerebrospinal fluid analysis:disease-related data patterns and evaluation programs.Journal of the Neurological Sciences,2001,184:101-122
61.de Pedro-Cuesta J,Petersen J,Stawiarz L et al.High levodopa use in periodically time-clustered,Icelandic birth cohorts.A vestige of parkinsonism etiology?Europarkinson Preparatory Activity Research Group.Acta Neurol Scand,1995,91:79-88.
62.de Pedro-Cuesta J,Gudmundsson G,Abraira Vet al.Whooping cough and Parkinson's disease.The Europarkinson Preparatory Activity Research Group.
63.Lontay B,Serfozo Z,Gergely P,et al.Localization of Myosin Phosphatase Target Subunit 1 in Rat Brain and in Primary Cultures of Neuronal Cells.J Comp Neurol,2004,478(1):72-87
1.Jing Zhang,David R.Goodlett.Proteomic approach to studying Parkinson's disease.Molecular Neurobiology,2004,29(3):271-288
2.Alison Abbott,Munich.Brain protein project enlists mice in 'dry run'.Nature,2003,425:110
3.Sandra I.Kim,Hans Voshol,Jan van Oostrum,et al.Neuroproteomics:expression profiling of the brain's proteomes in health and disease.Neurochem Res.2004, 29(6):1317-1331
4.S.M.Hague,S.Klaffke,O.Bandmann.Neurodegenerative disorders:Parkinson's disease and Huntington's disease.J Neurol Neurosurg Psychiatry,2005,76:1058-1063
5.Angela De Iuliis,Jessica Grigoletto,Alessandra Recchia,et al.A proteomic approach in the study of an animal model of Parkinson's disease.Clinica Chimica Acta,2005,357:202-209
6.Alves da Costa C.Recent advances on alpha-synuclein cell biology:functions and dysfunctions.Curr Mol Med,2003;3:17-24
7.Abeliovich A.,Schmitz Y.,Farinas I.,et al.Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.Neuron,2000,25:239-252
8.Kirik D.,Annett L.E.,Burger C.,et al.Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein:a new primate model of Parkinson's disease.Proc Natl Acad Sci USA,2003,100:2884-2889
9.Xu Jin.,Kao Shyan-Yuan,Lee Frank J.S.,et al.Dopamine-dependent neurotoxicity of alpha-synuclein:a mechanism for selective neurodegeneration in Parkinson disease.Nature Medicine,2002,8:600-606
10.Silvia Mandel,Edna Grunblatt,Peter Riederer,et al.Neuroprotective strategies in Parkinson's disease:an update on progress.CNS Drugs,2003,17(10):729-762
11.Joungil Choi,Allan I.Levey,Susan T.Weintraub,et al.Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases.J Biol Chem,2004,279(13):13256-13264
12.Miller D.W.,Ahmad R.,Hague S.,et al.L166P mutant DJ-1,causative for recessive Parkinson's disease,is degraded through the ubiquitin-proteasome system.J Biol Chem,2003,312:1342-1348
13.Ted M.Dawson,Valina L.Dawson.Molecular pathways of neurodegeneration in Parkinson's disease.Science,2003,302:819-822
14.J.A.Olzmann,K.Brown,K.D.Wilkinson.Familial Parkinson's diseaseassociated L166P mutation disrupts DJ-1 protein folding and function.J.Biol. Chem. 2004, 279:8506-8515
15. Bradford W. Gibson. The human mitochondrial proteome:oxidative stress, protein modifications and oxidative phosphorylation. The International Journal of Biochemistry & Cell Biology, 2005, 37:927-934
16. Jinghua Jin, Gloria E.Meredith, Leo Chen, et al. Quantitative proteomic analysis of mitochondrial proteins:relevance to Lewy body formation and Parkinson's disease. Molecular Brain Research, 2005,134:119-138
17. Valente E.M.,Abou-Sleiman P.M., Caputo V., et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 2004, 304:1158-1160
18. Pia Davidsson, Magnus Sjogren. The use of proteomics in biomarker discovery in neurodegenetative diseases. Disease Markers, 2005, 21(2):81-92
19. Erin J. Finehout, Zsofia Franck, Kelvin H.Lee. Complement protein isoforms in CSF as possible biomarkers for neurodegenerative disease. Disease Markers, 2005,21:93-101
20. M. Sjogren, L. Minthon, P. Davidsson, et al. CSF levels of tau, beta-amyloid(l-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging. Journal of Neural Transmission, 2000, 107:563-579
21. Magnus Sjogren, Pia Davidsson, Johan Gottfries, et al. The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process. Dement Geriatr Cogn Disord, 2001,12:257-264
22. Wenya Wang, Leyu Shi, Yuanbin Xie, et al. SP600125, a new JNK inhibitor,protects dopaminergic neurons in the MPTP model of Parkinson's disease. Neuroscience Research, 2004, 48:195-202
23. Peter M. Mathisen. Gene discovery and validation for neurodegenenerative dieases. DDT, 2003, 8(1):39-46
24. Maruyama W., Takahashi T. , Youdim M., et al. The anti-parkinson drug:rasagiline,prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH SY5Y cells. Journal of Neural Transmission, 2002, 109:467-481
25. Youdim M.B, Bar Am O, Yogev-Falach M, et al. Rasagiline:neurodegeneration, neuroprotection,and mitochondrial permeability transition.Journal of Neuroscience Research,2005,79(1-2):172-179
26.Yamada M,Mizuno Y,Mochizuki H.Parkin gene therapy for alpha-synucleinopathy:a rat model of Parkinson's disease.Hum Gene Ther,2005,16:262-270
27.Auluck PK,Meulener MC,Bonini NM.Mechanisms of suppression of alpha synulein neurotoxicity by geldanamycin in Drosophila.J Biol Chem,2005,280:2873-2878
1.Nancy M.B.,Benoit I.G.Snaring the function of α-synuclein.Cell,2005;123:359-361
2.Thomas D.K.,Eunjin C.,Hyangshuk R.,et al.α-synuclein has structural and functional similarities to small heat shock proteins.Biochemical and Biophysical Research Communication,2004;324:1352-1359
3.Anita S.,Christophe W.,Philippe V.α-synuclein regulation of the dopaminergic transporter:a possible role in the pathogenesis of Parkinson's disease.FEBS Letters,2004;565:1-5
4.McNaught K.S.P.,Olanow C.W.Protein aggregation in the pathogenesis of familial and sporadic Parkinson's disease.Neurobiology of Aging,2006;27:530-545
5.Elizabeta B.M.L.,Lan G.M.Pathophysiology of synuclein aggregation in Lewy body disease.Mechanisms of Ageing and Development,2006;127:188-202
6.Bennet M.C.The role of α-synuclein in neurodegenerative disease.Pharmacology & Therapeutics,2005;105:311-331
7.Dev K.K.,Hofele K.,Barbieri S.,et al.Part Ⅱ:α-synuclein and its molecular pathophysiological role in neurodegenerative disease.Neuropharmacology,2003;45:14-44
8.Tofaris G.K.,Razzaq A.,Ghetti B.,et al.Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function.J Biol Chem,2003;278:44405-44411.
9.Kumlesh K.D.,Herman P.,Bernd S.,et al.Part Ⅰ:Parkin-associated proteins and Parkinson's disease.Neuropharmacology,2003;45:1-13
10.Ignacio F.M.,Paul J.L.,Matthew J.F.Parkin genetics:one model for parkinson's disease.Human Molecular Genetics,2004;13:R127-R133
11.Shen J.,Cookson M.R.Mitochondria and dopamine:new insights into recessive Parkinsonism.Neuron,2004;43:301-304
12.Dawson T.M.,Dawson V.L.Molecular pathways of neurodegeneration in Parkinson'sdisease.Science,2003;302:819-822.
13.Sonia G.,Nicholas W.W.Molecular pathogenesis of Parkinson's disease.Human Molecular Genetics,2005;14(18):2749-2755
14.Cookson M.R..Pathways to Parkinsonism.Neuron,2003;37:7-10
15.Bandopadhyay R.,Kingsbury A.E.,Cookson M.R.,et al.The expression of DJ-1(PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain, 2004; 127:420-430
16. Sukhanov V.A., Ionov I.D., Piruzyan L.A. Neurodegenerative disorders:The role of genetic factors in their origin and the efficiency of treatment. Human Physiology, 2005; 31(4):472-482
17. Betarbet R., Sherer T.B., Greenamyre J.T. Ubiquitin-proteasome system and Parkinson's disease. Experimental Neurology, 2005; 191:S17-S27
18. Liu Y., Fallon L., Lashuel H.A.,et al. The UCHL1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility. Cell , 2002 ;111: 209-218.
19.Choi J., Levey A.I., Weintraub S.T., et al. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. 2004;279(13):13256-13264
20. Halbach O.B., Schober A., Krieglstein K. Genes, proteins, and neurotoxins involved in Parkinson's disease. Progress in Neurobiology, 2004; 73:151 -177
21. Bader V., Zhu X.R., Liibbert H., et al. Expression of DJ-1 in the adult mouse CNS. Brain Research, 2005; 1041:102-111
22. Zhang L., Shimoji M., Thomas B., et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1 implications for pathogenesis. Human Molecular Genetics, 2005; 14(14):2063-2073
23. Kotaria N., Hinz U., Zechel S. ,et al. Localization of DJ-1 protein in the murine brain . Cell Tissue Res ,2005;322: 503-507
24. Jin J., Meredith G..E. , Chen L., et al. Quantitative proteomic analysis of mitochondrial proteins:relevance to Lewy body formation and Parkinson's disease. Molecular Brain Research , 2005; 134:119-138
25. Valente E.M., Abou-Sleiman P.M., Caputo V., et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 2004; 304:1158-1160
26. Silvestri L., Caputo V., Bellacchio E., et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Human Molecular Genetics, 2005; 14(22):3477-3492
27. Pardo L.M., Duijn C.M.. In search of genes involved in neurodegenerative disorders . Mutation Research, 2005;592: 89-101
28.Guo L.X.,Wang W.,Chen S.G.Leucine-rich repeat kinase 2:Relevance to Parkinson's disease.The International Journal of Biochemistry & Cell Biology,2006;38:1469-1475
29.Mata I.F.,Wedemeyer W.J.,Farrer M.J.,et al.LRRK2 in Parkinson's disease:protein domains and functional insights.TRENDS in Neurosciences,2006;29(5):286-293
30.Hague S.M.,Klaffke S.,Bandmann O..Neurodegenerative disorders:Parkinson's disease and Huntington's disease.J Neurol Neurosurg Psychiatry,2005;76:1058-1063
2. Khachaturian Z.S. The challenges of developing and validating molecular and biochemical markers of Alzheimer's disease . Neurobiology of Aging , 2002, 23 :509-511
3. Pia Davidsson , Magnus Sjogren. The use of proteomics in biomarker discovery in neurodegenerative diseases. Disease Markers, 2005, 21: 81-92
4. Unlu M., Morgan M. E., and Minden J. S. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis, 1997, 18:2071-2077
5. Tonge R., Shaw J., Middleton B., et al. Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology. Proteomics, 2001,1:377-396
6. Richard E., Monteoliva L., Juarez S.,et al. Quantitative Analysis of Mitochondrial Protein Expression in Methylmalonic Acidemia by Two-Dimensional Difference Gel Electrophoresis. Journal of Proteome Research, 2006, 5:1602-1610
7. Nakano T., Ito M., Tanaka J., et al. Localization of the gene coding for myosin phosphatase, target subunit 1 (MYPT1) to human chromosome 12q15-q21. Genomics, 1997,44:150-152
8. Ito M. , Nakano T., Erdodi F.,et al. Myosin phosphatase: Structure, regulation and function. Molecular and Cellular Biochemistry, 2004, 259: 197-209
9. Lontay B, Serfozo Z , Gergely P, et al .Localization of Myosin Phosphatase Target Subunit 1 in Rat Brain and in Primary Cultures of Neuronal Cells. J Comp Neurol, 2004,478 (1) :72-87
10. Wu Y., Muranyi A., Erdodi F. et al. Localization of myosin phosphatase target subunit and its mutants. Journal of Muscle Research and Cell Motility , 2005,26:123-134
11. Wishart T. M, Parson S.H., and Gillingwater T. H. Synaptic Vulnerability in Neurodegenerative Disease. J Neuropathol Exp Neurol, 2006, 65(8): 733-739
12. Mukaetova-Ladinska E.B., McKeith I.G. Pathophysiology of synuclein aggregation in Lewy body disease. Mechanisms of Ageing and Development, 2006, 127:188-202
13.Suehiro T.,Yamamoto M.,Yoshida K.Increase of Plasma Proapolipoprotein A-I in Patients with Liver Cirrhosis and Its Relationship to Circulating High-Density Lipoproteins 2 and 3.Clinical Chemistry,1993,39(1):60-65
14.Ghiselli G,Gotto AM Jr,Tanenbaum S,et al.Proapolipoprotein A-I conversion kinetics in vivo in human and in rat.Proc.Natl.Acad.Sci.USA,1985,82(3):874-878
15.Chan D.C.and Watts G.F..Apolipoproteins as markers and managers of coronary risk.Q J Med,2006;99:277-287
16.Davidsson P.,Westman-Brinkmalm A.,Nilsson C.L.Proteome analysis of cerebrospinal fluid proteins in Alzheimer patients.NeuroReport,2002,13:611-615
17.Gursky O..Apolipoprotein structure and dynamics.Current Opinion in Lipidology,2005,16:287-294
18.Sorci-Thomas M.G.,Thomas M.J.The effects of altered apolipoprotein A-I structure on plasma HDL concentration.Trends Cardiovasc Med,2002,12:121-128.
19.Lotharius J.and Brundin P.Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.Human Molecular Genetics,2002,11(20):2395-2407
20.Song H,Saito K,Seishima M.,et al.Cerebrospinal fluid apoE and apoA-I concentrations in early- and late-onset Alzheimer's disease.Neurosci Lett,1997,231:175-178
21.Merched A,Xia Y,Visvikis S.,et al.Dereased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease.Neurobiol Aging,2000,21:27-30
1.Kim S.I.,Voshol H.,van Oostrum J.,et al.Neuroproteomics:expression profiling of the brain's proteomes in health and disease.Neurochem Res,2004,29(6):1317-1331
2.Hague S.M.,Klaffke S.,Bandmann O..Neurodegenerative disorders:Parkinson's disease and Huntington's disease.J Neurol Neurosurg Psychiatry,2005,76:1058-1063
3.Iuliis A.D.,Grigoletto J.,Recchia A.,et al.A proteomic approach in the study of an animal model of Parkinson's disease.Clinica Chimica Acta,2005,357:202-209
4.Volkmann J.Deep Brain Stimulation for the Treatment of Parkinson's Disease.J Clin Neurophysiol,2004;21:6-17
5.Walter BL,Vitek JL.Surgical treatment for Parkinson's disease.Lancet Neurol, 2004.3:719-728
6.杨晨,江澄川.脑深部刺激治疗帕金森病的疗效回顾.中华神经外科杂志,2006,22(5):319-321
7.姜秀峰,周晓平,胡小吾等.丘脑底核脑深部刺激术的参数设置及调整.中国微侵袭神经外科杂志.2006,11(3):105-107
8.McIntyre C.C.,Savasta M.,Walter B.L.,et al.How Does Deep Brain Stimulation Work? Present Understanding and Future Questions.J Clin Neurophysiol,2004;21:40-50
9.Hashimoto T,Elder CM,Okun MS,et al.Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons.J Neurosci,2003,23:1916-1923.
10.Jech R,Urgosik D,Tintera J,et al.Functional magnetic resonance imaging during deep brain stimulation:a pilot study in four patients with Parkinson's disease.Mov Disord,2001,16:1126-1132.
11.Jech R.Effects of deep brain stimulation of the STN and Vim nuclei under resting state and during simple movement task.A functional MRI study at 1.5 Tesla.Mov Disord,2002,17:S173.
12.Haslinger B,Boecker H,Buchel C,et al.Differential modulation of subcortical target and cortex during deep brain stimulation.Neuroimage,2003,18:517-524.
13.Goldfarb R.D.,Parrillo J.E..Complement.Crit Care Med,2005,33(12(Suppl.)):s482-s484
14.Reilly B.D..Structural comparison of human C4A3 and C4B1 after proteolytic activation by C1s.Molecular Immunology,2006,43:800-811
15.Law,S.K.A.,Dodds,A.W.,Porter,R.R..A comparison of the properties of two classes,C4A and C4B,of the human complement component C4.EMBO J,1984,3:1819-1823
16.Kasuya,H.Shimizu,T.Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage.Journal of Neurosurgery,1989,71(5 Pt 1):741-746
17.Michele Mussap and Mario Plebani.Biochemistry and Clinical Role of Human Cystatin C.Critical Reviews in Clinical Laboratory Sciences,2004,41(5-6):467-550
18.Merz GS,Benedikz E,Schwenk V,et al.Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells.J Cell Physiol,1997,173:423-32.
19. Bjamadottir M, Nilsson C, Lindstrom V, et al. The cerebral hemorrhage-producing cystatin C variant (L68Q) in extracellular fluids. Amyloid, 2001; 8: 1-10.
20. Ognibene A., Mannucci E., Caldini A., et al. Cystatin C reference values and aging. Clinical Biochemistry, 2006, 39:658-661
21. Brettschneider J., Riepe M.W., Petereit H.F.,et al. Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus? J Neurol Neurosurg Psychiatry, 2004. 75:1614-1616
22. Ruetschi U., Zetterberg H., Podust V. N., et al. Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF . Experimental Neurology, 2005, 196:273-281
23. Pasinetti G.M., Ungar L.H., Lange D.J., et al. Identification of potential CSF biomarkers in ALS. Neurology, 2006, 66:1218-1222
24. Carrette, O., Demalte, I., Scherl, A., et al. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics, 2003, 3:1486-1494.
25. Ghidoni R., Benussi L., Paterlini A., et al. Presenilin 2 mutations alter cystatin C trafficking in mouse primary neurons. Neurobiology of Aging , 2007, 28: 371-376
26. Natasa Kopitar-Jerala . The role of cystatins in cells of the immune system. FEBS Letters, 2006,580:6295-6301
27. Palm D. E., Knuckey N.W., Primiano M.J., et al. Cystatin C, a protease inhibitor, in degenerating rat hippocampal neurons following transient forebrain ischemia. Brain Research, 1995, 691: 1 -8
28. Deng A., Irizarry M.C., Nitsch R.M., et al. Elevation of cystatin C in susceptible neurons in Alzheimer's disease. Am J Pathol, 2001, 159: 1061-1068.
29. Ying G.-X., Huang C, Jiang Z.-H., et al. Up-regulation of cystatin C expression in the murine hippocampus following perforant path transaction . Neuroscience , 2002;112(2):289-298
30. Xu L., Sheng J.-S., Tang Z.-S, et al. Cystatin C prevents degeneration of rat nigral dopaminergic neurons: in vitro and in vivo studies. Neurobiology of Disease , 2005,18: 152-165
31. Pirttila T. J., Lukasiuk K., Hakansson K., et al.Cystatin C modulates neurodegeneration and neurogenesis following status epilepticus in mouse. Neurobiology of Disease, 2005.20 : 241-253
32. Nishiyama K., Konishi A., Nishio C, et al. Expression of cystatin C prevents oxidative stress-induced death in PC12 cells. Brain Research Bulletin, 2005, 67: 94-99
33. Levy E., Sastre M., Kumar A., et al. Codeposition of cystatin C with amyloid-beta protein in the brain of Alzheimer disease patients, J Neuropathol Exp Neurol, 2001,60:94-104.
34. Nagai A., Ryu J. K., Terashima M.., et al. Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B . Brain Research , 2005, 1066:120 - 128
35. Holtet TL, Graversen JH, Clemmensen I, et al. Tetranectin, a trimeric plasminogen-binding C type lectin. Protein Sci, 1997, 6:1511-1515.
36. Obrist P., Spizzo G, Ensinger C, et al. Aberrant tetranectin expression in human breast carcinomas as a predictor of survival. J Clin Pathol, 2004,57:417-421.
37. Wewer U.M. , Iba K. , Durkin M. E., et al. Tetranectin is a novel marker for myogenesis during embryonic development, muscle regeneration, and muscle cell differentiation in vitro. Dev Biol, 1998, 200: 247-259
38. Wewer UM, Ibaraki K, Schjorring P, et al. A potential role for tetranectin in mineralization during osteogenesis. J Cell Biol, 1994, 127:1767 - 1775.
39. Hogdall C.K. , Christiansen M, Norgaard-Pedersen B., et al. Plasma Tetranectin and Colorectal Cancer . European journal of Cancer ,1995, 31A (6): 888-894
40. Obrist P., Spizzo G, Ensinger C, et al. Aberrant tetranectin expression in human breast carcinomas as a predictor of survival. J Clin Pathol, 2004, 57:417-421.
41. Hammack BN, Fung KY, Hunsucker SW, et al. Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult Scler, 2004,10:245- 260.
42. Stoevring B., Jaliashvili I., Thougaard A.V., et al. Tetranectin in cerebrospinal fluid: Biochemical characterisation and evidence of intrathecal synthesis or selective uptake into CSF. Clinica Chimica Acta , 2005, 359: 65-71
43. Liu X.D., Zeng B.-F., Xu J.-G, et al. Proteomic analysis of the cerebrospinal fluid of patients with lumbar disk herniation. Proteomics, 2006, 6:1019-1028
44. Dietzmann, K., von Bossanyi P., Krause, D., et al. Expression of the plasminogen activator system and the inhibitors PAI-1 and PAI-2 in posttraumatic lesions of the CNS and brain injuries following dramatic circulatory arrests: an immunohistochemical study. Pathol Res Pract, 2000. 196 (1): 15-21
45. Zelko I.N., Mariani T. J., and Folz R. J. . Superoxide Dismutase Multigene Family: A Comparison of The CuZn-SOD (SOD1), Mn-SOD (SOD2), And EC-SOD (SOD3) Gene Structures, Evolution, And Expression. Free Radical Biology & Medicine, 2002, 33(3):337-349
46. Fattman C. L., Schaefer L. M, and Oury T.. Extracellular superoxide dismutase in biology and medicine. Free Radical Biology & Medicine, 2003, 35(3): 236-256
47. FolzR. J. , Guan J., Seldin M. F., et al. Mouse Extracellular Superoxide Dismutase: Primary Structure, Tissue-specific Gene Expression, Chromosomal Localization,and Lung In Situ Hybridization. Am J Respir Cell Mol Biol, 1997, 17:393-403.
48. Nakane H., Chu Y., Faraci F. M.,et al. Gene Transfer of Extracellular Superoxide Dismutase Increases Superoxide Dismutase Activity in Cerebrospinal Fluid. Stroke, 2001, 32:184-189
49. Oury T.D., Card J.P.,Klann, E. Localization of extracellular superoxide dismutase in adult mouse brain. Brain Res, 1999, 850:96-103
50. Rola R., Zou Y., Huang T-T, et al. Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radical Biology & Medicine, 2007,42:1133-1145
51. Sheng H., Bart R.D., Oury T.D., et al. Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience, 1999, 88:185-191
52. Hu D., Serrano F., Oury T.D., et al. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J Neurosci, 2006, 26: 3933- 3941
53. Watanabe Y, Chu Y, Andresen J. J., et al. Gene Transfer of Extracellular Superoxide Dismutase Reduces Cerebral Vasospasm After Subarachnoid Hemorrhage. Stroke, 2003, 34:434-440
54. Yamaguchi M., Zhou C, Heistad D. D., et al. Gene Transfer of Extracellular Superoxide Dismutase Failed to Prevent Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage. Stroke, 2004, 35:2512-2517
55. van Egmond M., Damen C.A., van Spriel A. B., et al. IgA and the IgA Fc receptor . TRENDS in Immunology , 2001, 22 (4): 205-211
56. Yoo E.M., Morrison S. L. IgA: An immune glycoprotein. Clinical Immunology, 2005, 116:3-10
57. Deisenhammer F., Bartos A., Egg R., et al. Guidelines on routine cerebrospinal fluid analysis.Report from an EFNS task Force.European Journal of Neurology,2006,13:913-922
58.Sobek O.,Adam P.On S.Seygert,V.Kunzmann,N.Schwertfeger,H.C.Koch,A.Faulstich:Determinants of lumbar CSF protein concentration.J Neurol,2003,250:371-372
59.Leary S.M.,McLean B.N.,Thompson E.J.Local synthesis of IgA in the cerebrospinal fluid of patients with neurological diseases.J Neurol,2000,247:609-615
60.Reiber H.,Peter J.B.Cerebrospinal fluid analysis:disease-related data patterns and evaluation programs.Journal of the Neurological Sciences,2001,184:101-122
61.de Pedro-Cuesta J,Petersen J,Stawiarz L et al.High levodopa use in periodically time-clustered,Icelandic birth cohorts.A vestige of parkinsonism etiology?Europarkinson Preparatory Activity Research Group.Acta Neurol Scand,1995,91:79-88.
62.de Pedro-Cuesta J,Gudmundsson G,Abraira Vet al.Whooping cough and Parkinson's disease.The Europarkinson Preparatory Activity Research Group.
63.Lontay B,Serfozo Z,Gergely P,et al.Localization of Myosin Phosphatase Target Subunit 1 in Rat Brain and in Primary Cultures of Neuronal Cells.J Comp Neurol,2004,478(1):72-87
1.Jing Zhang,David R.Goodlett.Proteomic approach to studying Parkinson's disease.Molecular Neurobiology,2004,29(3):271-288
2.Alison Abbott,Munich.Brain protein project enlists mice in 'dry run'.Nature,2003,425:110
3.Sandra I.Kim,Hans Voshol,Jan van Oostrum,et al.Neuroproteomics:expression profiling of the brain's proteomes in health and disease.Neurochem Res.2004, 29(6):1317-1331
4.S.M.Hague,S.Klaffke,O.Bandmann.Neurodegenerative disorders:Parkinson's disease and Huntington's disease.J Neurol Neurosurg Psychiatry,2005,76:1058-1063
5.Angela De Iuliis,Jessica Grigoletto,Alessandra Recchia,et al.A proteomic approach in the study of an animal model of Parkinson's disease.Clinica Chimica Acta,2005,357:202-209
6.Alves da Costa C.Recent advances on alpha-synuclein cell biology:functions and dysfunctions.Curr Mol Med,2003;3:17-24
7.Abeliovich A.,Schmitz Y.,Farinas I.,et al.Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.Neuron,2000,25:239-252
8.Kirik D.,Annett L.E.,Burger C.,et al.Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein:a new primate model of Parkinson's disease.Proc Natl Acad Sci USA,2003,100:2884-2889
9.Xu Jin.,Kao Shyan-Yuan,Lee Frank J.S.,et al.Dopamine-dependent neurotoxicity of alpha-synuclein:a mechanism for selective neurodegeneration in Parkinson disease.Nature Medicine,2002,8:600-606
10.Silvia Mandel,Edna Grunblatt,Peter Riederer,et al.Neuroprotective strategies in Parkinson's disease:an update on progress.CNS Drugs,2003,17(10):729-762
11.Joungil Choi,Allan I.Levey,Susan T.Weintraub,et al.Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases.J Biol Chem,2004,279(13):13256-13264
12.Miller D.W.,Ahmad R.,Hague S.,et al.L166P mutant DJ-1,causative for recessive Parkinson's disease,is degraded through the ubiquitin-proteasome system.J Biol Chem,2003,312:1342-1348
13.Ted M.Dawson,Valina L.Dawson.Molecular pathways of neurodegeneration in Parkinson's disease.Science,2003,302:819-822
14.J.A.Olzmann,K.Brown,K.D.Wilkinson.Familial Parkinson's diseaseassociated L166P mutation disrupts DJ-1 protein folding and function.J.Biol. Chem. 2004, 279:8506-8515
15. Bradford W. Gibson. The human mitochondrial proteome:oxidative stress, protein modifications and oxidative phosphorylation. The International Journal of Biochemistry & Cell Biology, 2005, 37:927-934
16. Jinghua Jin, Gloria E.Meredith, Leo Chen, et al. Quantitative proteomic analysis of mitochondrial proteins:relevance to Lewy body formation and Parkinson's disease. Molecular Brain Research, 2005,134:119-138
17. Valente E.M.,Abou-Sleiman P.M., Caputo V., et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 2004, 304:1158-1160
18. Pia Davidsson, Magnus Sjogren. The use of proteomics in biomarker discovery in neurodegenetative diseases. Disease Markers, 2005, 21(2):81-92
19. Erin J. Finehout, Zsofia Franck, Kelvin H.Lee. Complement protein isoforms in CSF as possible biomarkers for neurodegenerative disease. Disease Markers, 2005,21:93-101
20. M. Sjogren, L. Minthon, P. Davidsson, et al. CSF levels of tau, beta-amyloid(l-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging. Journal of Neural Transmission, 2000, 107:563-579
21. Magnus Sjogren, Pia Davidsson, Johan Gottfries, et al. The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process. Dement Geriatr Cogn Disord, 2001,12:257-264
22. Wenya Wang, Leyu Shi, Yuanbin Xie, et al. SP600125, a new JNK inhibitor,protects dopaminergic neurons in the MPTP model of Parkinson's disease. Neuroscience Research, 2004, 48:195-202
23. Peter M. Mathisen. Gene discovery and validation for neurodegenenerative dieases. DDT, 2003, 8(1):39-46
24. Maruyama W., Takahashi T. , Youdim M., et al. The anti-parkinson drug:rasagiline,prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH SY5Y cells. Journal of Neural Transmission, 2002, 109:467-481
25. Youdim M.B, Bar Am O, Yogev-Falach M, et al. Rasagiline:neurodegeneration, neuroprotection,and mitochondrial permeability transition.Journal of Neuroscience Research,2005,79(1-2):172-179
26.Yamada M,Mizuno Y,Mochizuki H.Parkin gene therapy for alpha-synucleinopathy:a rat model of Parkinson's disease.Hum Gene Ther,2005,16:262-270
27.Auluck PK,Meulener MC,Bonini NM.Mechanisms of suppression of alpha synulein neurotoxicity by geldanamycin in Drosophila.J Biol Chem,2005,280:2873-2878
1.Nancy M.B.,Benoit I.G.Snaring the function of α-synuclein.Cell,2005;123:359-361
2.Thomas D.K.,Eunjin C.,Hyangshuk R.,et al.α-synuclein has structural and functional similarities to small heat shock proteins.Biochemical and Biophysical Research Communication,2004;324:1352-1359
3.Anita S.,Christophe W.,Philippe V.α-synuclein regulation of the dopaminergic transporter:a possible role in the pathogenesis of Parkinson's disease.FEBS Letters,2004;565:1-5
4.McNaught K.S.P.,Olanow C.W.Protein aggregation in the pathogenesis of familial and sporadic Parkinson's disease.Neurobiology of Aging,2006;27:530-545
5.Elizabeta B.M.L.,Lan G.M.Pathophysiology of synuclein aggregation in Lewy body disease.Mechanisms of Ageing and Development,2006;127:188-202
6.Bennet M.C.The role of α-synuclein in neurodegenerative disease.Pharmacology & Therapeutics,2005;105:311-331
7.Dev K.K.,Hofele K.,Barbieri S.,et al.Part Ⅱ:α-synuclein and its molecular pathophysiological role in neurodegenerative disease.Neuropharmacology,2003;45:14-44
8.Tofaris G.K.,Razzaq A.,Ghetti B.,et al.Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function.J Biol Chem,2003;278:44405-44411.
9.Kumlesh K.D.,Herman P.,Bernd S.,et al.Part Ⅰ:Parkin-associated proteins and Parkinson's disease.Neuropharmacology,2003;45:1-13
10.Ignacio F.M.,Paul J.L.,Matthew J.F.Parkin genetics:one model for parkinson's disease.Human Molecular Genetics,2004;13:R127-R133
11.Shen J.,Cookson M.R.Mitochondria and dopamine:new insights into recessive Parkinsonism.Neuron,2004;43:301-304
12.Dawson T.M.,Dawson V.L.Molecular pathways of neurodegeneration in Parkinson'sdisease.Science,2003;302:819-822.
13.Sonia G.,Nicholas W.W.Molecular pathogenesis of Parkinson's disease.Human Molecular Genetics,2005;14(18):2749-2755
14.Cookson M.R..Pathways to Parkinsonism.Neuron,2003;37:7-10
15.Bandopadhyay R.,Kingsbury A.E.,Cookson M.R.,et al.The expression of DJ-1(PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain, 2004; 127:420-430
16. Sukhanov V.A., Ionov I.D., Piruzyan L.A. Neurodegenerative disorders:The role of genetic factors in their origin and the efficiency of treatment. Human Physiology, 2005; 31(4):472-482
17. Betarbet R., Sherer T.B., Greenamyre J.T. Ubiquitin-proteasome system and Parkinson's disease. Experimental Neurology, 2005; 191:S17-S27
18. Liu Y., Fallon L., Lashuel H.A.,et al. The UCHL1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility. Cell , 2002 ;111: 209-218.
19.Choi J., Levey A.I., Weintraub S.T., et al. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. 2004;279(13):13256-13264
20. Halbach O.B., Schober A., Krieglstein K. Genes, proteins, and neurotoxins involved in Parkinson's disease. Progress in Neurobiology, 2004; 73:151 -177
21. Bader V., Zhu X.R., Liibbert H., et al. Expression of DJ-1 in the adult mouse CNS. Brain Research, 2005; 1041:102-111
22. Zhang L., Shimoji M., Thomas B., et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1 implications for pathogenesis. Human Molecular Genetics, 2005; 14(14):2063-2073
23. Kotaria N., Hinz U., Zechel S. ,et al. Localization of DJ-1 protein in the murine brain . Cell Tissue Res ,2005;322: 503-507
24. Jin J., Meredith G..E. , Chen L., et al. Quantitative proteomic analysis of mitochondrial proteins:relevance to Lewy body formation and Parkinson's disease. Molecular Brain Research , 2005; 134:119-138
25. Valente E.M., Abou-Sleiman P.M., Caputo V., et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 2004; 304:1158-1160
26. Silvestri L., Caputo V., Bellacchio E., et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Human Molecular Genetics, 2005; 14(22):3477-3492
27. Pardo L.M., Duijn C.M.. In search of genes involved in neurodegenerative disorders . Mutation Research, 2005;592: 89-101
28.Guo L.X.,Wang W.,Chen S.G.Leucine-rich repeat kinase 2:Relevance to Parkinson's disease.The International Journal of Biochemistry & Cell Biology,2006;38:1469-1475
29.Mata I.F.,Wedemeyer W.J.,Farrer M.J.,et al.LRRK2 in Parkinson's disease:protein domains and functional insights.TRENDS in Neurosciences,2006;29(5):286-293
30.Hague S.M.,Klaffke S.,Bandmann O..Neurodegenerative disorders:Parkinson's disease and Huntington's disease.J Neurol Neurosurg Psychiatry,2005;76:1058-1063