自噬在神经突起退化过程中的作用及自噬溶酶体在突起内的动力学研究
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摘要
神经元轴突和树突(或统称为“突起”)的退化是一个自我消亡的过程,其死亡方式有别于神经元胞体的凋亡,并在神经系统发育过程中起着至关重要的作用。在众多神经系统退行性疾病中,突起退化现象频繁出现,且时常早于神经元胞体死亡,甚至会引发胞体死亡,导致患者的行为功能障碍。尽管如此,人们对于突起退化调控机制尚知之甚少。
自噬是细胞的代谢方式之一,在饥饿条件下,细胞通过蛋白降解,使细胞质中物质和细胞器得以循环利用。研究结果表明,自噬与神经退行性疾病有关,而自噬在这些疾病中起着促进细胞死亡还是维持细胞存活的作用,尚存在着争议。而自噬是如何调控神经突起退化的也还不清楚。
本课题通过运用小鼠颈上神经节(superior cervical ganglion, SCG)神经元,研究自噬在不同方式诱导的神经突起退化过程中的作用。研究发现,在体外瓦勒氏变性、神经生长因子(nerve growth factor, NGF)剥夺以及微管干扰引发的交感神经元突起退化过程中,均伴随着自噬的诱发。突起退化时,自噬体／自噬溶酶体和瓦解的骨架蛋白一起堆积在突起串珠中。自噬诱发标志之一的微管相关蛋白轻链Ⅱ(microtubule-associated protein light chain 3-Ⅱ, LC3-Ⅱ)的表达水平在突起退化早期显著上调。而自噬抑制剂3-甲基腺嘌呤(3-Methyladenine,3-MA)可以有效阻止突起活性的丧失,维持线粒体功能,并抑制突起退化现象。此外,通过RNA干扰下调自噬关键基因atg7和beclinl的表达水平显著缓解了NGF剥夺导致的突起退化；低表达Atg7还可以抑制体外瓦勒氏变性诱发的突起退化。
此外,在血清剥夺后的PC12细胞突起中,我们也同样观察到了自噬溶酶体的蓄积。利用荧光漂泊恢复技术,发现mRFP-LC3标记的自噬溶酶体在活细胞中是运动的结构。PC12细胞的实时荧光成像实验进一步证实了自噬溶酶体在细胞内沿着突起作顺向和逆向运输,它们在运动过程中时常停顿,有时还会改变方向。通过计算机图像处理,对自噬溶酶体运动的特征参数进行了定量分析,研究发现自噬溶酶体运动的平均速度与其囊泡大小相关,直径大的自噬溶酶体运动相对缓慢；直径较小的自噬溶酶体沿突起快速运动,2 min内运动位移在5μm以上的囊泡顺、逆向运动的平均速度分别约为0.33μm/s和0.39μm／s,而最快运动速度则分别可达1.22μm／s和1.51μm/s,2 min内可跟踪到的长距离转运的囊泡连续运动50μm以上。微管干扰剂破坏微管结构后,自噬溶酶体停止运动,提示自噬溶酶体的运输依赖于微管。而添加分子马达蛋白kinesin或dynein的阻断剂也同样影响着自噬溶酶体在突起内的顺、逆向运输。
综上所述,本课题的研究取得了以下创新性成果：①揭示了神经突起退化过程伴随着自噬的诱发,自噬活性在突起病变早期显著上升；②添加自噬抑制剂或下调自噬相关基因atg7或beclinl的表达,可有效延缓突起退化；③通过活细胞荧光成像技术,发现并记录了自噬溶酶体在PC12细胞突起内进行顺逆向快速运输的动态过程,运用计算机图像处理手段定量系统的分析了运动的特征参数；④运用荧光双标记技术,直观的显示自噬溶酶体沿微管进行运动。分子马达kinesin和dynein分别介导着自噬溶酶体的顺、逆向运输。本课题结合细胞分子生物学、活细胞荧光成像技术以及计算机图像处理手段,系统阐述自噬在神经突起退化过程中的作用,并全面分析了自噬溶酶体在突起内的动力学特征,在国内外尚未见报道。研究结果提示自噬对神经元突起退化起着重要的调控作用,为更好地理解轴突和树突死亡机制提供线索,并为开发全新治疗手段提供实验基础。
Axon and dendrite (or neurite) degeneration plays a critical role during development of the nervous system, which is recognized as a self-destructive programme and distinct from somata apoptotic death. It occurs commonly in a wide range of neurodegenerative disorders. Neurite degeneration often precedes and sometimes leads to the death of cell soma, and may make a more important contribution to the patient's disability. Nevertheless, the mechanisms of neurite degeneration are poorly known.
Autophagy is a well-characterized catabolic mechanism whereby cells degrade proteins and recycle cytoplasmic components and intracellular organelles in response to nutrient starvation. Accumulating evidence shows that autophagy has been linked to various human neurodegenerative diseases, while the existence of autophagy as a prodeath or prosurvival pathway is controversial and the mechanism by which autophagy programmes neurites to die is still unclear.
We here investigated the involvement of the autophagic process in neurite degeneration induced by different experimental paradigms in mouse superior cervical ganglion (SCG) neurons. Our present study revealed the induction of autophagy in degenerating neurites of sympathetic neuron initiated by three different experimental paradigms, including in vitro Wallerian degeneration, nerve growth factor (NGF) deprivation and microtubule disruption. Autophagosomes/autolysosomes colocalized with collapsed cytoskeletal proteins in neuritic beadings during degeneration. Upregulation of microtubule-associated protein light chain 3-Ⅱ(LC3-Ⅱ), which is the most reliable marker for autophagy, was observed during the early stage of neurite degeneration. The autophagy inhibitor 3-Methyladenine (3-MA) efficiently suppressed neurite degeneration by protecting neurites from the loss of viability and mitochondrial function. Furthermore, knocking down the key autophagy-related gene atg7 or beclinl by RNA interference significantly delayed axonal and dendritic degeneration after NGF deprivation. Reduced expression of Atg7 also suppressed neurite fragmentation after transection.
The accumulation of autolysosomes was also observed in neurites of PC12 cells after serum deprivation. In addition, fluorescence recovery after photobleaching (FRAP) technique showed the monomeric red fluorescence protein (mRFP)-LC3-labeled autolysosomes were motile in living cells. Real-time fluorescence imaging of serum-deprived PC 12 cells further demonstrated that autolysosomes moved along neurites in both anterograde and retrograde directions. They paused, re-started, and sometimes changed directions. By using image processing, quantitative analysis was made to show the dynamic biophysical characteristics of these vesicles. The speed of autolysosomes varied in size, as the movement of larger autolysosomes was relatively slow. Those small autolysosomes traveled along neurites in anterograde and retrograde directions rapidly, with an average velocity of approximately 0.33μm/s and 0.39μm/s respectively. The maximal speeds of anterograde and retrograde transport were 1.22μm/s and 1.51μm/s, and the maximal displacement of long-range moving autolysosomes we traced was longer than 50μm in 2 min. Disruption of microtubules by nocodazole completely abolished their movements, suggesting the neuritic transport of autolysosomes depends on microtubules. The directional transport of autolysosomes was also particularly affected by application of dynein or kinesin inhibitor.
Collectively, our present study achieved the following novel findings:1) Induction of autophagy occurred during the early stage of neurite degeneration; 2) Application of autophagy inhibitor or knocking down the autophagy-related genes atg7 or beclinl significantly delayed neurite degeneration; 3) By using live-cell fluorescent imaging system, we found that autolysosomes moved along PC 12 neurites in both anterograde and retrograde directions. The highly dynamic movement of autolysosomes was traced and their biophysical characteristics were analyzed by image processing.4) Fluorescent double-label studies showed autolysosomes depended on microtubules for neuritic transport. Molecular motors kinesin and dynein regulated the anterograde and retrograde transport of autolysosomes respectively. Combined use of molecular and cellular biology, live cell imaging techniques and computer image processing allowed us to demonstrate the effect of autophagy during neurite degeneration and systematically describe the dynamics of autolysosomes in neurites for the first time. These results suggest the critical role of autophagy in neurite degeneration and may provide a valuable clue in understanding the mechanism of axonal and dendritic degeneration, which is pivotal for the development of new therapeutic approaches.
自噬是细胞的代谢方式之一,在饥饿条件下,细胞通过蛋白降解,使细胞质中物质和细胞器得以循环利用。研究结果表明,自噬与神经退行性疾病有关,而自噬在这些疾病中起着促进细胞死亡还是维持细胞存活的作用,尚存在着争议。而自噬是如何调控神经突起退化的也还不清楚。
本课题通过运用小鼠颈上神经节(superior cervical ganglion, SCG)神经元,研究自噬在不同方式诱导的神经突起退化过程中的作用。研究发现,在体外瓦勒氏变性、神经生长因子(nerve growth factor, NGF)剥夺以及微管干扰引发的交感神经元突起退化过程中,均伴随着自噬的诱发。突起退化时,自噬体／自噬溶酶体和瓦解的骨架蛋白一起堆积在突起串珠中。自噬诱发标志之一的微管相关蛋白轻链Ⅱ(microtubule-associated protein light chain 3-Ⅱ, LC3-Ⅱ)的表达水平在突起退化早期显著上调。而自噬抑制剂3-甲基腺嘌呤(3-Methyladenine,3-MA)可以有效阻止突起活性的丧失,维持线粒体功能,并抑制突起退化现象。此外,通过RNA干扰下调自噬关键基因atg7和beclinl的表达水平显著缓解了NGF剥夺导致的突起退化；低表达Atg7还可以抑制体外瓦勒氏变性诱发的突起退化。
此外,在血清剥夺后的PC12细胞突起中,我们也同样观察到了自噬溶酶体的蓄积。利用荧光漂泊恢复技术,发现mRFP-LC3标记的自噬溶酶体在活细胞中是运动的结构。PC12细胞的实时荧光成像实验进一步证实了自噬溶酶体在细胞内沿着突起作顺向和逆向运输,它们在运动过程中时常停顿,有时还会改变方向。通过计算机图像处理,对自噬溶酶体运动的特征参数进行了定量分析,研究发现自噬溶酶体运动的平均速度与其囊泡大小相关,直径大的自噬溶酶体运动相对缓慢；直径较小的自噬溶酶体沿突起快速运动,2 min内运动位移在5μm以上的囊泡顺、逆向运动的平均速度分别约为0.33μm/s和0.39μm／s,而最快运动速度则分别可达1.22μm／s和1.51μm/s,2 min内可跟踪到的长距离转运的囊泡连续运动50μm以上。微管干扰剂破坏微管结构后,自噬溶酶体停止运动,提示自噬溶酶体的运输依赖于微管。而添加分子马达蛋白kinesin或dynein的阻断剂也同样影响着自噬溶酶体在突起内的顺、逆向运输。
综上所述,本课题的研究取得了以下创新性成果：①揭示了神经突起退化过程伴随着自噬的诱发,自噬活性在突起病变早期显著上升；②添加自噬抑制剂或下调自噬相关基因atg7或beclinl的表达,可有效延缓突起退化；③通过活细胞荧光成像技术,发现并记录了自噬溶酶体在PC12细胞突起内进行顺逆向快速运输的动态过程,运用计算机图像处理手段定量系统的分析了运动的特征参数；④运用荧光双标记技术,直观的显示自噬溶酶体沿微管进行运动。分子马达kinesin和dynein分别介导着自噬溶酶体的顺、逆向运输。本课题结合细胞分子生物学、活细胞荧光成像技术以及计算机图像处理手段,系统阐述自噬在神经突起退化过程中的作用,并全面分析了自噬溶酶体在突起内的动力学特征,在国内外尚未见报道。研究结果提示自噬对神经元突起退化起着重要的调控作用,为更好地理解轴突和树突死亡机制提供线索,并为开发全新治疗手段提供实验基础。
Axon and dendrite (or neurite) degeneration plays a critical role during development of the nervous system, which is recognized as a self-destructive programme and distinct from somata apoptotic death. It occurs commonly in a wide range of neurodegenerative disorders. Neurite degeneration often precedes and sometimes leads to the death of cell soma, and may make a more important contribution to the patient's disability. Nevertheless, the mechanisms of neurite degeneration are poorly known.
Autophagy is a well-characterized catabolic mechanism whereby cells degrade proteins and recycle cytoplasmic components and intracellular organelles in response to nutrient starvation. Accumulating evidence shows that autophagy has been linked to various human neurodegenerative diseases, while the existence of autophagy as a prodeath or prosurvival pathway is controversial and the mechanism by which autophagy programmes neurites to die is still unclear.
We here investigated the involvement of the autophagic process in neurite degeneration induced by different experimental paradigms in mouse superior cervical ganglion (SCG) neurons. Our present study revealed the induction of autophagy in degenerating neurites of sympathetic neuron initiated by three different experimental paradigms, including in vitro Wallerian degeneration, nerve growth factor (NGF) deprivation and microtubule disruption. Autophagosomes/autolysosomes colocalized with collapsed cytoskeletal proteins in neuritic beadings during degeneration. Upregulation of microtubule-associated protein light chain 3-Ⅱ(LC3-Ⅱ), which is the most reliable marker for autophagy, was observed during the early stage of neurite degeneration. The autophagy inhibitor 3-Methyladenine (3-MA) efficiently suppressed neurite degeneration by protecting neurites from the loss of viability and mitochondrial function. Furthermore, knocking down the key autophagy-related gene atg7 or beclinl by RNA interference significantly delayed axonal and dendritic degeneration after NGF deprivation. Reduced expression of Atg7 also suppressed neurite fragmentation after transection.
The accumulation of autolysosomes was also observed in neurites of PC12 cells after serum deprivation. In addition, fluorescence recovery after photobleaching (FRAP) technique showed the monomeric red fluorescence protein (mRFP)-LC3-labeled autolysosomes were motile in living cells. Real-time fluorescence imaging of serum-deprived PC 12 cells further demonstrated that autolysosomes moved along neurites in both anterograde and retrograde directions. They paused, re-started, and sometimes changed directions. By using image processing, quantitative analysis was made to show the dynamic biophysical characteristics of these vesicles. The speed of autolysosomes varied in size, as the movement of larger autolysosomes was relatively slow. Those small autolysosomes traveled along neurites in anterograde and retrograde directions rapidly, with an average velocity of approximately 0.33μm/s and 0.39μm/s respectively. The maximal speeds of anterograde and retrograde transport were 1.22μm/s and 1.51μm/s, and the maximal displacement of long-range moving autolysosomes we traced was longer than 50μm in 2 min. Disruption of microtubules by nocodazole completely abolished their movements, suggesting the neuritic transport of autolysosomes depends on microtubules. The directional transport of autolysosomes was also particularly affected by application of dynein or kinesin inhibitor.
Collectively, our present study achieved the following novel findings:1) Induction of autophagy occurred during the early stage of neurite degeneration; 2) Application of autophagy inhibitor or knocking down the autophagy-related genes atg7 or beclinl significantly delayed neurite degeneration; 3) By using live-cell fluorescent imaging system, we found that autolysosomes moved along PC 12 neurites in both anterograde and retrograde directions. The highly dynamic movement of autolysosomes was traced and their biophysical characteristics were analyzed by image processing.4) Fluorescent double-label studies showed autolysosomes depended on microtubules for neuritic transport. Molecular motors kinesin and dynein regulated the anterograde and retrograde transport of autolysosomes respectively. Combined use of molecular and cellular biology, live cell imaging techniques and computer image processing allowed us to demonstrate the effect of autophagy during neurite degeneration and systematically describe the dynamics of autolysosomes in neurites for the first time. These results suggest the critical role of autophagy in neurite degeneration and may provide a valuable clue in understanding the mechanism of axonal and dendritic degeneration, which is pivotal for the development of new therapeutic approaches.
引文
1. Medana IM & Esiri MM (2003) Axonal damage:a key predictor of outcome in human CNS diseases. Brain 126,515-530.
2. Waller A (1850) Experiments on the section of glossopharyngeal and hypoglossal nerves of the frog and observations of the alternatives produced thereby in the structure of their primitive fibers. Philos Trans R Soc Lond B Biol Sci 140,423-429.
3. Griffin JW, George EB & Chaudhry V (1996) Wallerian degeneration in peripheral nerve disease. Baillieres Clin Neurol 5,65-75.
4. Finn JT, Weil M, Archer F, Siman R, Srinivasan A & Raff MC (2000) Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases. JNeurosci 20,1333-1341.
5. Cavanagh JB (1964) The significance of the "dying back" process in experimental and human neurological disease. Int Rev Exp Pathol 3,219-267.
6. Azzouz M, Leclerc N, Gurney M, Warter JM, Poindron P & Borg J (1997) Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis. Muscle Nerve 20,45-51.
7. Iseki E, Kato M, Marui W, Ueda K & Kosaka K (2001) A neuropathological study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies. J Neurol Sci 185,129-134.
8. Raff MC, Whitmore AV & Finn JT (2002) Axonal self-destruction and neurodegeneration. Science 296,868-871.
9. Campenot RB (1982) Development of sympathetic neurons in compartmentalized cultures. Ⅱ. Local control of neurite survival by nerve growth factor. Dev Biol 93, 13-21.
10. Mandelkow EM & Mandelkow E (1998) Tau in Alzheimer's disease. Trends Cell Biol 8,425-427.
11. Hirano A, Donnenfeld H, Sasaki S & Nakano I (1984) Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43,461-470.
12. Braak H, Sandmann-Keil D, Gai W & Braak E (1999) Extensive axonal Lewy neurites in Parkinson's disease:a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Neurosci Lett 265,67-69.
13. Li H, Li SH, Yu ZX, Shelbourne P & Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. JNeurosci 21,8473-8481.
14. Bjartmar C & Trapp BD (2001) Axonal and neuronal degeneration in multiple sclerosis:mechanisms and functional consequences. Curr Opin Neurol 14,271-278.
15. O'Leary DD & Koester SE (1993) Development of projection neuron types, axon pathways, and patterned connections of the mammalian cortex. Neuron 10,991-1006.
16. Park JS, Bateman MC & Goldberg MP (1996) Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation. Neurobiol Dis 3,215-227.
17. Roediger B & Armati PJ (2003) Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis 13,222-229.
18. Ikegaya Y, Kim JA, Baba M, Iwatsubo T, Nishiyama N & Matsuki N (2001) Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation:implication for a cellular defense against excitotoxicity. J Cell Sci 114,4083-4093.
19. Zhu B, Luo L, Moore GR, Paty DW & Cynader MS (2003) Dendritic and synaptic pathology in experimental autoimmune encephalomyelitis. Am J Pathol 162, 1639-1650.
20. Emery DG & Lucas LH (1995) Ultrastructural damage and neuritic beading in cold-stressed spinal neurons with comparisons to NMDA and A23187 toxicity. Brain Res 692,161-173.
21. Fayaz I & Tator CH (2000) Modeling axonaL injury in vitro:injury and regeneration following acute neuritic trauma. J Neurosci Methods 102,69-79.
22. Ikegami K, Kato S & Koike T (2004) N-alpha-p-L-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration. Brain Res 1030,81-93.
23. Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L & He Z (2003) Involvement of the ubiquitin-proteasome system in the early stages of Wallerian degeneration. Neuron 39,217-225.
24. Berliocchi L, Fava E, Leist M, Horvat V, Dinsdale D, Read D & Nicotera P (2005) Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis. J Cell Biol 168,607-618.
25. Ikegami K & Koike T (2003) Non-apoptotic neurite degeneration in apoptotic neuronal death:pivotal role of mitochondrial function in neurites. Neuroscience 122, 617-626.
26. MacInnis BL & Campenot RB (2005) Regulation of Wallerian degeneration and nerve growth factor withdrawal-induced pruning of axons of sympathetic neurons by the proteasome and the MEK/Erk pathway. Mol Cell Neurosci 28,430-439.
27. Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW & Sanes JR (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28,41-51.
28. Conforti L, Tarlton A, Mack TG, Mi W, Buckmaster EA, Wagner D,Perry VH & Coleman MP (2000) A Ufd2/D4Cole le chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc Natl Acad Sci USA 97, 11377-11382.
29. Lunn ER, Perry VH, Brown MC, Rosen H & Gordon S (1989). Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve. Eur J Neurosci 1,27-33.
30. Laser H, Conforti L, Morreale G, Mack TG, Heyer M, Haley JE, Wishart TM, Beirowski B, Walker SA, Haase G, Celik A, Adalbert R, Wagner D, Grumme D, Ribchester RR, Plomann M & Coleman MP (2006) The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus. Mol Biol Cell 17,1075-1084.
31. Mi W, Beirowski B, Gillingwater TH, Adalbert R, Wagner D, Grumme D, Osaka H, Conforti L, Arnhold S, Addicks K, Wada K, Ribchester RR & Coleman MP (2005) The slow Wallerian degeneration-gene, WldS, inhibits axonal-spheroid pathology in gracile axonal dystrophy mice. Brain 128,405-416.
32. Coleman MP (2005) Axon degeneration mechanisms:commonality amid diversity. Nat Rev Neurosci 6,889-898.
33. Ferri A, Sanes JR, Coleman MP, Cunningham JM & Kato AC (2003) Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr Biol 13,669-673.
34. Hirokawa N & Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6,201-14. 35. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y & Hirokawa N (2001) Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105,587-597.
36. Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabe de Angelis M, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE & Fisher EM (2003) Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808-812.
37. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI & Roberts GW (1993) (3-amyloid precursor protein (β APP) as a marker for axonal injury after head injury. Neurosci Lett 160,139-144.
38. Ferguson B, Matyszak MK, Esiri MM & Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120,393-399.
39. Iwata A, Stys PK, Wolf JA, Chen XH, Taylor AQ Meaney DF & Smith DH (2004) Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. J Neurosci 24, 4605-4613.
40. Kapoor R, Davies M, Blaker PA, Hall SM & Smith KJ (2003) Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol 53,174-180.
41. Stys PK (1998) Anoxic and ischemic injury of myelinated axons in CNS white matter:from mechanistic concepts to therapeutics. J Cereb Blood Flow Metab 18, 2-25.
42. Mizushima N, Levine B, Cuervo AM & Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451,1069-1075.
43. Eskelinen EL (2004) Macroautophagy in mammalian cells. In:P. Saftig, editor. Lysosomes. Georgetown, TX:Landes Bioscience/Eurekah.Com.
44. Papadopoulos T & Pfeifer U (1986) Regression of rat liver autophagic vacuoles by locally applied cycloheximide. Lab Invest 54,100-107.
45. Reggiori F & Klionsky DJ (2002) Autophagy in the eukaryotic cell. Eukaryot. Cell 1,11-21.
46. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M & Ohsumi Y (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5,539-545.
47. Rubinsztein DC, Gestwicki JE, Murphy LO & Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6,304-312.
48. Yang YP, Liang ZQ, Gu ZL & Qin ZH (2005) Molecular mechanism and regulation of autophagy. Acta Pharmacol Sin 26,1421-1434.
49. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y & Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19,5720-5728.
50. Mizushima N, Yamamoto A,Matsui M, Yoshimori T & Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15,1101-1111.
51. Seglen PO & Gordon PB (1982) 3-methyladenine:Specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 79,1889-1892.
52. Gozuacik D & Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78, 217-245.
53. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB & Tsujimoto Y (2004) Role of Bcl-2 family of proteins in non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6, 1221-1228.
54. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH & Lenardo MJ (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304,1500-1502.
55. Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y & Jung YK (2005) Essential roles of Atg5 and FADD in autophagic cell death:dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 280,20722-20729.
56. Mizushima N (2004) Methods for monitoring autophagy. Int J Biochem Cell Biol 36,2491-2502.
57. Kneen M, Farinas J, Li Y & Verkman AS (1998) Green fluorescent protein as a noninvasive intracellular pH indicator. Biophys J74,1591-1599.
58. Campbell RE, Tour O, Palmer AE, Steinbach PA, Baird GS, Zacharias DA & Tsien RY (2002) A monomeric red fluorescent protein. Proc Natl Acad Sci U S A 99, 7877-7882.
59. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H & Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171,603-614.
60. Kimura S, Noda T & Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3,452-460.
61. Biederbick A, Kern HF & Elsasser HP (1995) Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. Eur J of Cell Biol 66,3-14.
62. Chu CT (2006) Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 65,423-432.
63. Cherra SJ & Chu CT (2008) Autophagy in neuroprotection and neurodegeneration: a question of balance. Future Neurol 3,309-323.
64. Bergamini E, Cavallini G, Donati A & Gori Z (2004) The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases. Int J Biochem Cell Biol 36,2392-2404.
65. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH & Taylor JP (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447,859-863.
66. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D & Cuervo AM (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118,777-788.
67. Shintani T & Klionsky DJ (2004) Autophagy in health and disease:a double-edged sword. Science 306,990-995.
68. Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L & Tolkovsky A (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1,11-22.
69. Nixon RA (2006) Autophagy in neurodegenerative disease:friend, foe or turncoat? Trends Neurosci 29,528-535.
70. Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P & Sulzer D (2001) Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet 10, 1243-1254.
71. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H & Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889.
72. Komatsu M, Waguri S, Chiba T, Murata S, Iwata JI, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E & Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441,880-884.
73. Juhasz G, Erdi B, Sass M & Neufeld TP (2007) Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 21,3061-3066.
74. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B & Wyss-Coray T (2008) The autophagy protein beclin 1 is reduced in early Alzheimer's disease and regulates Aβ accumulation in vivo. J Clin Invest 118,2190-2199.
75. Ravikumar B, Duden R & Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11,1107-1117.
76. Webb JL, Ravikumar B, Atkins J, Skepper JN & Rubinsztein DC (2003) a-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278, 25009-25013.
77. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ & Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36,585-595.
78. Caldero J, Tarabal O, Casanovas A, Ciutat D, Casas C, Llado J & Esquerda JE (2007) Excitotoxic motoneuron disease in chick embryo evolves with autophagic neurodegeneration and deregulation of neuromuscular innervation. JNeurosci Res 85, 2726-2740.
79. Tarabal O, Caldero J, Casas C, Oppenheim RW & Esquerda JE (2005) Protein retention in the ndoplasmic reticulum, blockade of programmed cell death and autophagy selectively occur in spinal cord motoneurons after glutamate receptor-mediated injury. Mol Cell Neurosci 29,283-298.
80. Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, Kawahara N, Kuida K, Nagata S, Kominami E, Tanaka K & Uchiyama Y (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am JPathol 172,454-469.
81. Florez-McClure ML, Linseman DA, Chu CT, Barker PA, Bouchard RJ, Le SS, Laessig TA & Heidenreich KA (2004) The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. JNeurosci 24,4498-4509.
82. Gomez-Santos C, Ferrer I, Santidrian AF, Barrachina M, Gil J & Ambrosio S (2003) Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res 73,341-350.
83. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM & Nixon RA (2005) Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 171,87-98.
84. Zhu JH, Guo F, Shelburne J, Watkins S & Chu CT (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol 13,473-481.
85. Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, Dunn RS, Vorhees CV, Wills-Karp M, Degen JL, Davis RJ, Mizushima N, Rakic P, Dardzinski BJ, Holland SK, Sharp FR & Kuan CY (2006) Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am JPathol 169,566-583.
86. Sikorska B, Liberski PP, Giraud P, Kopp N & Brown P (2004) Autophagy is a part of ultrastructural synaptic pathology in Greutzfeldt-Jakob disease:a brain biopsy study. Int JBiochem Cell Biol 36,2563-2573.
87. Yue Z, Horton A, BravinM, DeJager PL, Selimi F & Heintz N (2002) A novel protein complex linking the delta 2 glutamate receptor and autophagy:implications for neurodegeneration in lurcher mice. Neuron 35,921-933.
88. Trivedi N, Marsh P, Goold RG, Wood-Kaczmar A & Gordon-Weeks PR (2005) Glycogen synthase kinase-3beta phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons. J Cell Sci 118,993-1005.
89. Wang QJ, Ding Y, Kohtz DS, Mizushima N, Cristea IM, Rout MP, Chait BT, Zhong Y, Heintz N & Yue Z (2006) Induction of autophagy in axonal dystrophy and degeneration. JNeurosci 26,8057-8068.
90. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K & Yue Z (2007) Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci USA 104,14489-14494.
91. Nishiyama J, Miura E, Mizushima N, Watanabe M & Yuzaki M (2007) Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy 3,591-596.
92. Rowland AM, Richmond JE, Olsen JG, Hall DH & Bamber BA (2006) Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans. JNeurosci 26,1711-1720.
93. Zeng M & Zhou JN (2008) Roles of autophagy and mTOR signaling in neuronal differentiation of mouse neuroblastoma cells. Cell Signal 20,659-665.
94. Gong R, Park CS, Abbassi NR & Tang SJ (2006) Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. JBiol Chem 281,18802-18815.
95. Griffin JW, George EB, Hsieh ST & Glass JD (1995) Axonal degeneration and other disorders of the axonal cytoskeleton. In:The Axon, S.W. Waxman, J.D. Kocsis, and P.K. Stys, eds. (New York:Oxford University Press), pp.375-390.
96. Rabacchi SA, Ensini M, Bonfanti L, Gravina A & Maffei L (1994) Nerve growth factor reduces apoptosis of axotomized retinal ganglion cells in neonatal rat. Neuroscience 63,969-973.
97. Wang MS, Wu Y, Culver DG & Glass JD (2000) Pathogenesis of axonal degeneration:parallels between wallerian degeneration and vincristine neuropathy. J Neuropathol Exp Neurol 59,599-606.
98. Wang MS, Davis AA, Culver DG & Glass JD (2002) Wlds mice are resistant to paclitaxel (Taxol) neuropathy. Ann Neurol 52,442-447.
99. He Y & Baas PW (2003) Growing and working with peripheral neurons. Methods Cell Biol 71,17-35.
100. Laser H, Mack T, Wagner D & Coleman M (2003) Proteasome inhibition arrests neurite outgrowth and causes "dying-back" degeneration in primary culture. J Neurosci Res 74,906-916.
101. Yang Y, Kawataki T, Fukui K & Koike T (2007) Cellular Zn2+ chelators cause "dying-back" neurite degeneration associated with energy impairment. J Neurosci Res 85,2844-2855.
102. Xue L, Fletcher GC & Tolkovsky AM (1999) Autophagy is activated by apoptotic signalling in sympathetic neurons:an alternative mechanism of death execution. Mol Cell Neurosci 14,180-198.
103. Emery DG & Lucas JH (1995) Ultrastructural damage and neuritic beading in cold-stressed spinal neurons with comparisons to NMDA and A23187 toxicity. Brain Res 692,161-173.
104. Takeuchi H, Mizuno T, Zhang GQ, Wang JY, Kawanokuchi J, Kuno R & Suzumura A (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. JBiol Chem 280,10444-10454.
105. Touma E, Kato S, Fukui K & Koike T (2007) Calpain-mediated cleavage of collapsing response mediator protein-2 (CRMP-2) during neurite degeneration. Eur J Neurosci 26,3368-3381.
106. Klionsky DJ (2005) The molecular machinery of autophagy:unanswered questions. J Cell Sci 118,7-18.
107. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H & Meijer AJ (1997) The phosphatidylinositol 3-kinase inhibitors wortmannin and LY 294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243,240-246.
108. Petiot A, Ogier-Denis E, Blommaart EFC, Meijers AJ & Codogno P (2000) Distinct classes of phosphatidylinositol 3'-kinases are involved in signalling pathways that control macroautophagy in HT-29 cells. JBiol Chem 275,992-998.
109. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K & Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature 411,494-498.
110. Harper SQ & Gonzalez-Alegre P (2008) Lentivirus-mediated RNA interference in mammalian neurons. Methods Mol Biol 442,95-112.
111. Furuya D, Tsuji N, Yagihashi A & Watanabe N (2005) Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 307,26-40.
112. Ullman E, Fan Y, Stawowczyk M, Chen HM, Yue Z & Zong WX (2008) Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress. Cell Death Differ 15,422-425.
113. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B & Levine B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72,8586-8596.
114. Diskin T, Tal-Or P, Erlich S, Mizrachy L, Alexandrovich A, Shohami E & Pinkas-Kramarski R (2005) Closed head injury induces upregulation of Beclin 1 at the cortical site of injury. J Neurotrauma 22,750-762.
115. Goodwin JS & Kenworthy AK (2005) Photobleaching approaches to investigate diffusional mobility and trafficking of Ras in living cells. Methods 37,154-164.
116. Vallee RB & Bloom GS (1991) Mechanisms of fast and slow axonal transport. Annu Rev Neurosci 14,59-92.
117. Roy S, Winton MJ, Black MM, Trojanowski JQ & Lee VM (2007) Rapid and intermittent cotransport of slow component-b proteins. J Neurosci 27,3131-3138.
118. Ohkuma S & Poole B (1978) Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA 75,3327-3331.
119. Fukuda M (1991) Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular trafficking. JBiol Chem 266,21327-21330.
120. Jahreiss L, Menzies FM & Rubinsztein DC (2008) The itinerary of autophagosomes:from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9,574-587.
121. Fuger P, Behrends LB, Mertel S, Sigrist SJ & Rasse TM (2007) Live imaging of synapse development and measuring protein dynamics using two-color fluorescence recovery after photo-bleaching at Drosophila synapses. Nat Protoc 2,3285-3298.
122. Sbalzarini IF & Koumoutsakos P (2005) Feature point tracking and trajectory analysis for video imaging in cell biology. J Struct Biol 151,182-195.
123. Cheezum MK, Walker WF & Guilford WH (2001) Quantitative comparison of algorithms for tracking single fluorescent particles. Biophys J81,2378-2388.
124. Contento AL, Xiong Y & Bassham DC (2005) Visualization of autophagy in Arabidopsis using the fluorescent dye monodansylcadaverine and a GFP-AtATG8e fusion protein. Plant J 42,598-608.
125. Fass E, Shvets E, Degani I, Hirschberg K & Elazar Z (2006) Microtubules support production of starvation-induced autophagosomes but not their targeting and fusion with lysosomes. JBiol Chem 281,36303-36316.
126. Kimura S, Noda T & Yoshimori T (2008) Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct Funct 33, 109-122.
127. Yue ZY (2007) Regulation of neuronal autophagy in axon:implication of autophagy in axonal function and dysfunction/degeneration. Autophagy 3,139-141.
128. Katsumata K, Nishiyama J, Inoue T, Mizushima N, Takeda J & Yuzaki M (2010) Dynein-and activity-dependent retrograde transport of autophagosomes in neuronal axons. Autophagy 6,1-8.
129. Kochl R, Hu XW, Chan EY & Tooze SA (2006) Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7, 129-145.
130. Bananis E, Murray JW, Stockert RJ, Satir P & Wolkoff AW (2000) Microtubule and motor-dependent endocytic vesicle sorting in vitro. J Cell Biol 151,179-186.
131. Ekstrom P & Kanje M (1984) Inhibition of fast axonal transport by erythro-9-[3-(2-hydroxynonyl)] adenine. JNeurochem 43,1342-1345.
132. Reunanen H, Marttinen M & Hirsimaki P (1988) Effects of griseofulvin and Nocodazole on the accumulation of autophagic vacuoles in Ehrlich ascites tumor cells. Exp Mol Pathol 48,97-102.
133. Aplin A, Jasionowski T, Tuttle DL, Lenk SE & Dunn WAJ (1992) Cytoskeletal elements are required for the formation and maturation of autophagic vacuoles. J Cell Physiol 152,458-466.
134. Millecamps S, Gowing G, Corti O, Mallet J & Julien JP (2007) Conditional NF-L transgene expression in mice for in vivo analysis of turnover and transport rate of neurofilaments. JNeurosci 27,4947-4956.
2. Waller A (1850) Experiments on the section of glossopharyngeal and hypoglossal nerves of the frog and observations of the alternatives produced thereby in the structure of their primitive fibers. Philos Trans R Soc Lond B Biol Sci 140,423-429.
3. Griffin JW, George EB & Chaudhry V (1996) Wallerian degeneration in peripheral nerve disease. Baillieres Clin Neurol 5,65-75.
4. Finn JT, Weil M, Archer F, Siman R, Srinivasan A & Raff MC (2000) Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases. JNeurosci 20,1333-1341.
5. Cavanagh JB (1964) The significance of the "dying back" process in experimental and human neurological disease. Int Rev Exp Pathol 3,219-267.
6. Azzouz M, Leclerc N, Gurney M, Warter JM, Poindron P & Borg J (1997) Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis. Muscle Nerve 20,45-51.
7. Iseki E, Kato M, Marui W, Ueda K & Kosaka K (2001) A neuropathological study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies. J Neurol Sci 185,129-134.
8. Raff MC, Whitmore AV & Finn JT (2002) Axonal self-destruction and neurodegeneration. Science 296,868-871.
9. Campenot RB (1982) Development of sympathetic neurons in compartmentalized cultures. Ⅱ. Local control of neurite survival by nerve growth factor. Dev Biol 93, 13-21.
10. Mandelkow EM & Mandelkow E (1998) Tau in Alzheimer's disease. Trends Cell Biol 8,425-427.
11. Hirano A, Donnenfeld H, Sasaki S & Nakano I (1984) Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43,461-470.
12. Braak H, Sandmann-Keil D, Gai W & Braak E (1999) Extensive axonal Lewy neurites in Parkinson's disease:a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Neurosci Lett 265,67-69.
13. Li H, Li SH, Yu ZX, Shelbourne P & Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. JNeurosci 21,8473-8481.
14. Bjartmar C & Trapp BD (2001) Axonal and neuronal degeneration in multiple sclerosis:mechanisms and functional consequences. Curr Opin Neurol 14,271-278.
15. O'Leary DD & Koester SE (1993) Development of projection neuron types, axon pathways, and patterned connections of the mammalian cortex. Neuron 10,991-1006.
16. Park JS, Bateman MC & Goldberg MP (1996) Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation. Neurobiol Dis 3,215-227.
17. Roediger B & Armati PJ (2003) Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis 13,222-229.
18. Ikegaya Y, Kim JA, Baba M, Iwatsubo T, Nishiyama N & Matsuki N (2001) Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation:implication for a cellular defense against excitotoxicity. J Cell Sci 114,4083-4093.
19. Zhu B, Luo L, Moore GR, Paty DW & Cynader MS (2003) Dendritic and synaptic pathology in experimental autoimmune encephalomyelitis. Am J Pathol 162, 1639-1650.
20. Emery DG & Lucas LH (1995) Ultrastructural damage and neuritic beading in cold-stressed spinal neurons with comparisons to NMDA and A23187 toxicity. Brain Res 692,161-173.
21. Fayaz I & Tator CH (2000) Modeling axonaL injury in vitro:injury and regeneration following acute neuritic trauma. J Neurosci Methods 102,69-79.
22. Ikegami K, Kato S & Koike T (2004) N-alpha-p-L-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration. Brain Res 1030,81-93.
23. Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L & He Z (2003) Involvement of the ubiquitin-proteasome system in the early stages of Wallerian degeneration. Neuron 39,217-225.
24. Berliocchi L, Fava E, Leist M, Horvat V, Dinsdale D, Read D & Nicotera P (2005) Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis. J Cell Biol 168,607-618.
25. Ikegami K & Koike T (2003) Non-apoptotic neurite degeneration in apoptotic neuronal death:pivotal role of mitochondrial function in neurites. Neuroscience 122, 617-626.
26. MacInnis BL & Campenot RB (2005) Regulation of Wallerian degeneration and nerve growth factor withdrawal-induced pruning of axons of sympathetic neurons by the proteasome and the MEK/Erk pathway. Mol Cell Neurosci 28,430-439.
27. Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW & Sanes JR (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28,41-51.
28. Conforti L, Tarlton A, Mack TG, Mi W, Buckmaster EA, Wagner D,Perry VH & Coleman MP (2000) A Ufd2/D4Cole le chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc Natl Acad Sci USA 97, 11377-11382.
29. Lunn ER, Perry VH, Brown MC, Rosen H & Gordon S (1989). Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve. Eur J Neurosci 1,27-33.
30. Laser H, Conforti L, Morreale G, Mack TG, Heyer M, Haley JE, Wishart TM, Beirowski B, Walker SA, Haase G, Celik A, Adalbert R, Wagner D, Grumme D, Ribchester RR, Plomann M & Coleman MP (2006) The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus. Mol Biol Cell 17,1075-1084.
31. Mi W, Beirowski B, Gillingwater TH, Adalbert R, Wagner D, Grumme D, Osaka H, Conforti L, Arnhold S, Addicks K, Wada K, Ribchester RR & Coleman MP (2005) The slow Wallerian degeneration-gene, WldS, inhibits axonal-spheroid pathology in gracile axonal dystrophy mice. Brain 128,405-416.
32. Coleman MP (2005) Axon degeneration mechanisms:commonality amid diversity. Nat Rev Neurosci 6,889-898.
33. Ferri A, Sanes JR, Coleman MP, Cunningham JM & Kato AC (2003) Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr Biol 13,669-673.
34. Hirokawa N & Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6,201-14. 35. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y & Hirokawa N (2001) Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105,587-597.
36. Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabe de Angelis M, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE & Fisher EM (2003) Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808-812.
37. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI & Roberts GW (1993) (3-amyloid precursor protein (β APP) as a marker for axonal injury after head injury. Neurosci Lett 160,139-144.
38. Ferguson B, Matyszak MK, Esiri MM & Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120,393-399.
39. Iwata A, Stys PK, Wolf JA, Chen XH, Taylor AQ Meaney DF & Smith DH (2004) Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. J Neurosci 24, 4605-4613.
40. Kapoor R, Davies M, Blaker PA, Hall SM & Smith KJ (2003) Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol 53,174-180.
41. Stys PK (1998) Anoxic and ischemic injury of myelinated axons in CNS white matter:from mechanistic concepts to therapeutics. J Cereb Blood Flow Metab 18, 2-25.
42. Mizushima N, Levine B, Cuervo AM & Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451,1069-1075.
43. Eskelinen EL (2004) Macroautophagy in mammalian cells. In:P. Saftig, editor. Lysosomes. Georgetown, TX:Landes Bioscience/Eurekah.Com.
44. Papadopoulos T & Pfeifer U (1986) Regression of rat liver autophagic vacuoles by locally applied cycloheximide. Lab Invest 54,100-107.
45. Reggiori F & Klionsky DJ (2002) Autophagy in the eukaryotic cell. Eukaryot. Cell 1,11-21.
46. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M & Ohsumi Y (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5,539-545.
47. Rubinsztein DC, Gestwicki JE, Murphy LO & Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6,304-312.
48. Yang YP, Liang ZQ, Gu ZL & Qin ZH (2005) Molecular mechanism and regulation of autophagy. Acta Pharmacol Sin 26,1421-1434.
49. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y & Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19,5720-5728.
50. Mizushima N, Yamamoto A,Matsui M, Yoshimori T & Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15,1101-1111.
51. Seglen PO & Gordon PB (1982) 3-methyladenine:Specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 79,1889-1892.
52. Gozuacik D & Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78, 217-245.
53. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB & Tsujimoto Y (2004) Role of Bcl-2 family of proteins in non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6, 1221-1228.
54. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH & Lenardo MJ (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304,1500-1502.
55. Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y & Jung YK (2005) Essential roles of Atg5 and FADD in autophagic cell death:dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 280,20722-20729.
56. Mizushima N (2004) Methods for monitoring autophagy. Int J Biochem Cell Biol 36,2491-2502.
57. Kneen M, Farinas J, Li Y & Verkman AS (1998) Green fluorescent protein as a noninvasive intracellular pH indicator. Biophys J74,1591-1599.
58. Campbell RE, Tour O, Palmer AE, Steinbach PA, Baird GS, Zacharias DA & Tsien RY (2002) A monomeric red fluorescent protein. Proc Natl Acad Sci U S A 99, 7877-7882.
59. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H & Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171,603-614.
60. Kimura S, Noda T & Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3,452-460.
61. Biederbick A, Kern HF & Elsasser HP (1995) Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. Eur J of Cell Biol 66,3-14.
62. Chu CT (2006) Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 65,423-432.
63. Cherra SJ & Chu CT (2008) Autophagy in neuroprotection and neurodegeneration: a question of balance. Future Neurol 3,309-323.
64. Bergamini E, Cavallini G, Donati A & Gori Z (2004) The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases. Int J Biochem Cell Biol 36,2392-2404.
65. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH & Taylor JP (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447,859-863.
66. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D & Cuervo AM (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118,777-788.
67. Shintani T & Klionsky DJ (2004) Autophagy in health and disease:a double-edged sword. Science 306,990-995.
68. Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L & Tolkovsky A (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1,11-22.
69. Nixon RA (2006) Autophagy in neurodegenerative disease:friend, foe or turncoat? Trends Neurosci 29,528-535.
70. Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P & Sulzer D (2001) Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet 10, 1243-1254.
71. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H & Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889.
72. Komatsu M, Waguri S, Chiba T, Murata S, Iwata JI, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E & Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441,880-884.
73. Juhasz G, Erdi B, Sass M & Neufeld TP (2007) Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 21,3061-3066.
74. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B & Wyss-Coray T (2008) The autophagy protein beclin 1 is reduced in early Alzheimer's disease and regulates Aβ accumulation in vivo. J Clin Invest 118,2190-2199.
75. Ravikumar B, Duden R & Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11,1107-1117.
76. Webb JL, Ravikumar B, Atkins J, Skepper JN & Rubinsztein DC (2003) a-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278, 25009-25013.
77. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ & Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36,585-595.
78. Caldero J, Tarabal O, Casanovas A, Ciutat D, Casas C, Llado J & Esquerda JE (2007) Excitotoxic motoneuron disease in chick embryo evolves with autophagic neurodegeneration and deregulation of neuromuscular innervation. JNeurosci Res 85, 2726-2740.
79. Tarabal O, Caldero J, Casas C, Oppenheim RW & Esquerda JE (2005) Protein retention in the ndoplasmic reticulum, blockade of programmed cell death and autophagy selectively occur in spinal cord motoneurons after glutamate receptor-mediated injury. Mol Cell Neurosci 29,283-298.
80. Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, Kawahara N, Kuida K, Nagata S, Kominami E, Tanaka K & Uchiyama Y (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am JPathol 172,454-469.
81. Florez-McClure ML, Linseman DA, Chu CT, Barker PA, Bouchard RJ, Le SS, Laessig TA & Heidenreich KA (2004) The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. JNeurosci 24,4498-4509.
82. Gomez-Santos C, Ferrer I, Santidrian AF, Barrachina M, Gil J & Ambrosio S (2003) Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res 73,341-350.
83. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM & Nixon RA (2005) Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 171,87-98.
84. Zhu JH, Guo F, Shelburne J, Watkins S & Chu CT (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol 13,473-481.
85. Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, Dunn RS, Vorhees CV, Wills-Karp M, Degen JL, Davis RJ, Mizushima N, Rakic P, Dardzinski BJ, Holland SK, Sharp FR & Kuan CY (2006) Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am JPathol 169,566-583.
86. Sikorska B, Liberski PP, Giraud P, Kopp N & Brown P (2004) Autophagy is a part of ultrastructural synaptic pathology in Greutzfeldt-Jakob disease:a brain biopsy study. Int JBiochem Cell Biol 36,2563-2573.
87. Yue Z, Horton A, BravinM, DeJager PL, Selimi F & Heintz N (2002) A novel protein complex linking the delta 2 glutamate receptor and autophagy:implications for neurodegeneration in lurcher mice. Neuron 35,921-933.
88. Trivedi N, Marsh P, Goold RG, Wood-Kaczmar A & Gordon-Weeks PR (2005) Glycogen synthase kinase-3beta phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons. J Cell Sci 118,993-1005.
89. Wang QJ, Ding Y, Kohtz DS, Mizushima N, Cristea IM, Rout MP, Chait BT, Zhong Y, Heintz N & Yue Z (2006) Induction of autophagy in axonal dystrophy and degeneration. JNeurosci 26,8057-8068.
90. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K & Yue Z (2007) Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci USA 104,14489-14494.
91. Nishiyama J, Miura E, Mizushima N, Watanabe M & Yuzaki M (2007) Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy 3,591-596.
92. Rowland AM, Richmond JE, Olsen JG, Hall DH & Bamber BA (2006) Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans. JNeurosci 26,1711-1720.
93. Zeng M & Zhou JN (2008) Roles of autophagy and mTOR signaling in neuronal differentiation of mouse neuroblastoma cells. Cell Signal 20,659-665.
94. Gong R, Park CS, Abbassi NR & Tang SJ (2006) Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. JBiol Chem 281,18802-18815.
95. Griffin JW, George EB, Hsieh ST & Glass JD (1995) Axonal degeneration and other disorders of the axonal cytoskeleton. In:The Axon, S.W. Waxman, J.D. Kocsis, and P.K. Stys, eds. (New York:Oxford University Press), pp.375-390.
96. Rabacchi SA, Ensini M, Bonfanti L, Gravina A & Maffei L (1994) Nerve growth factor reduces apoptosis of axotomized retinal ganglion cells in neonatal rat. Neuroscience 63,969-973.
97. Wang MS, Wu Y, Culver DG & Glass JD (2000) Pathogenesis of axonal degeneration:parallels between wallerian degeneration and vincristine neuropathy. J Neuropathol Exp Neurol 59,599-606.
98. Wang MS, Davis AA, Culver DG & Glass JD (2002) Wlds mice are resistant to paclitaxel (Taxol) neuropathy. Ann Neurol 52,442-447.
99. He Y & Baas PW (2003) Growing and working with peripheral neurons. Methods Cell Biol 71,17-35.
100. Laser H, Mack T, Wagner D & Coleman M (2003) Proteasome inhibition arrests neurite outgrowth and causes "dying-back" degeneration in primary culture. J Neurosci Res 74,906-916.
101. Yang Y, Kawataki T, Fukui K & Koike T (2007) Cellular Zn2+ chelators cause "dying-back" neurite degeneration associated with energy impairment. J Neurosci Res 85,2844-2855.
102. Xue L, Fletcher GC & Tolkovsky AM (1999) Autophagy is activated by apoptotic signalling in sympathetic neurons:an alternative mechanism of death execution. Mol Cell Neurosci 14,180-198.
103. Emery DG & Lucas JH (1995) Ultrastructural damage and neuritic beading in cold-stressed spinal neurons with comparisons to NMDA and A23187 toxicity. Brain Res 692,161-173.
104. Takeuchi H, Mizuno T, Zhang GQ, Wang JY, Kawanokuchi J, Kuno R & Suzumura A (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. JBiol Chem 280,10444-10454.
105. Touma E, Kato S, Fukui K & Koike T (2007) Calpain-mediated cleavage of collapsing response mediator protein-2 (CRMP-2) during neurite degeneration. Eur J Neurosci 26,3368-3381.
106. Klionsky DJ (2005) The molecular machinery of autophagy:unanswered questions. J Cell Sci 118,7-18.
107. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H & Meijer AJ (1997) The phosphatidylinositol 3-kinase inhibitors wortmannin and LY 294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243,240-246.
108. Petiot A, Ogier-Denis E, Blommaart EFC, Meijers AJ & Codogno P (2000) Distinct classes of phosphatidylinositol 3'-kinases are involved in signalling pathways that control macroautophagy in HT-29 cells. JBiol Chem 275,992-998.
109. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K & Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature 411,494-498.
110. Harper SQ & Gonzalez-Alegre P (2008) Lentivirus-mediated RNA interference in mammalian neurons. Methods Mol Biol 442,95-112.
111. Furuya D, Tsuji N, Yagihashi A & Watanabe N (2005) Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 307,26-40.
112. Ullman E, Fan Y, Stawowczyk M, Chen HM, Yue Z & Zong WX (2008) Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress. Cell Death Differ 15,422-425.
113. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B & Levine B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72,8586-8596.
114. Diskin T, Tal-Or P, Erlich S, Mizrachy L, Alexandrovich A, Shohami E & Pinkas-Kramarski R (2005) Closed head injury induces upregulation of Beclin 1 at the cortical site of injury. J Neurotrauma 22,750-762.
115. Goodwin JS & Kenworthy AK (2005) Photobleaching approaches to investigate diffusional mobility and trafficking of Ras in living cells. Methods 37,154-164.
116. Vallee RB & Bloom GS (1991) Mechanisms of fast and slow axonal transport. Annu Rev Neurosci 14,59-92.
117. Roy S, Winton MJ, Black MM, Trojanowski JQ & Lee VM (2007) Rapid and intermittent cotransport of slow component-b proteins. J Neurosci 27,3131-3138.
118. Ohkuma S & Poole B (1978) Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA 75,3327-3331.
119. Fukuda M (1991) Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular trafficking. JBiol Chem 266,21327-21330.
120. Jahreiss L, Menzies FM & Rubinsztein DC (2008) The itinerary of autophagosomes:from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9,574-587.
121. Fuger P, Behrends LB, Mertel S, Sigrist SJ & Rasse TM (2007) Live imaging of synapse development and measuring protein dynamics using two-color fluorescence recovery after photo-bleaching at Drosophila synapses. Nat Protoc 2,3285-3298.
122. Sbalzarini IF & Koumoutsakos P (2005) Feature point tracking and trajectory analysis for video imaging in cell biology. J Struct Biol 151,182-195.
123. Cheezum MK, Walker WF & Guilford WH (2001) Quantitative comparison of algorithms for tracking single fluorescent particles. Biophys J81,2378-2388.
124. Contento AL, Xiong Y & Bassham DC (2005) Visualization of autophagy in Arabidopsis using the fluorescent dye monodansylcadaverine and a GFP-AtATG8e fusion protein. Plant J 42,598-608.
125. Fass E, Shvets E, Degani I, Hirschberg K & Elazar Z (2006) Microtubules support production of starvation-induced autophagosomes but not their targeting and fusion with lysosomes. JBiol Chem 281,36303-36316.
126. Kimura S, Noda T & Yoshimori T (2008) Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct Funct 33, 109-122.
127. Yue ZY (2007) Regulation of neuronal autophagy in axon:implication of autophagy in axonal function and dysfunction/degeneration. Autophagy 3,139-141.
128. Katsumata K, Nishiyama J, Inoue T, Mizushima N, Takeda J & Yuzaki M (2010) Dynein-and activity-dependent retrograde transport of autophagosomes in neuronal axons. Autophagy 6,1-8.
129. Kochl R, Hu XW, Chan EY & Tooze SA (2006) Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7, 129-145.
130. Bananis E, Murray JW, Stockert RJ, Satir P & Wolkoff AW (2000) Microtubule and motor-dependent endocytic vesicle sorting in vitro. J Cell Biol 151,179-186.
131. Ekstrom P & Kanje M (1984) Inhibition of fast axonal transport by erythro-9-[3-(2-hydroxynonyl)] adenine. JNeurochem 43,1342-1345.
132. Reunanen H, Marttinen M & Hirsimaki P (1988) Effects of griseofulvin and Nocodazole on the accumulation of autophagic vacuoles in Ehrlich ascites tumor cells. Exp Mol Pathol 48,97-102.
133. Aplin A, Jasionowski T, Tuttle DL, Lenk SE & Dunn WAJ (1992) Cytoskeletal elements are required for the formation and maturation of autophagic vacuoles. J Cell Physiol 152,458-466.
134. Millecamps S, Gowing G, Corti O, Mallet J & Julien JP (2007) Conditional NF-L transgene expression in mice for in vivo analysis of turnover and transport rate of neurofilaments. JNeurosci 27,4947-4956.