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Abstract

Autophagy is a conserved catabolic process that delivers the cytosol and cytosolic constituents to the lysosome. Its fundamental role is to maintain cellular homeostasis and to protect cells from varying insults, including misfolded proteins and damaged organelles. Beyond these roles, the highly specialized cells of the brain have further adapted autophagic pathways to suit their distinct needs. In this review, we briefly summarize our current understanding of the different forms of autophagy and then offer a closer look at how these pathways impact neuronal and glial functions. The emerging evidence indicates that not only are autophagy pathways essential for neural health, but they have a direct impact on developmental and neurodegenerative processes. Taken together, as we unravel the complex roles autophagy pathways play, we will gain the necessary insight to modify these pathways to protect the human brain and treat neurodegenerative diseases.

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2014-07-08
2024-04-15
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Literature Cited

  1. Alirezaei M, Kemball CC, Flynn CT, Wood MR, Whitton JL, Kiosses WB. 2010. Short-term fasting induces profound neuronal autophagy. Autophagy 6:702–10 [Google Scholar]
  2. Arroyo DS, Soria JA, Gaviglio EA, Garcia-Keller C, Cancela LM. et al. 2013. Toll-like receptor 2 ligands promote microglial cell death by inducing autophagy. FASEB J. 27:299–312 [Google Scholar]
  3. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL. et al. 2008. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182:685–701 [Google Scholar]
  4. Baba M, Osumi M, Scott SV, Klionsky DJ, Ohsumi Y. 1997. Two distinct pathways for targeting proteins from the cytoplasm to the vacuole/lysosome. J. Cell Biol. 139:1687–95 [Google Scholar]
  5. Baba M, Takeshige K, Baba N, Ohsumi Y. 1994. Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization. J. Cell Biol. 124:903–13 [Google Scholar]
  6. Backer JM, Bourret L, Dice JF. 1983. Regulation of catabolism of microinjected ribonuclease A requires the amino-terminal 20 amino acids. Proc. Natl. Acad. Sci. USA 80:2166–70 [Google Scholar]
  7. Bains M, Florez-McClure ML, Heidenreich KA. 2009. Insulin-like growth factor-I prevents the accumulation of autophagic vesicles and cell death in Purkinje neurons by increasing the rate of autophagosome-to-lysosome fusion and degradation. J. Biol. Chem. 284:20398–407 [Google Scholar]
  8. Ban BK, Jun MH, Ryu HH, Jang DJ, Ahmad ST, Lee JA. 2013. Autophagy negatively regulates early axon growth in cortical neurons. Mol. Cell. Biol. 33:3907–19 [Google Scholar]
  9. Behrends C, Sowa ME, Gygi SP, Harper JW. 2010. Network organization of the human autophagy system. Nature 466:68–76 [Google Scholar]
  10. Bejarano E, Cuervo AM. 2010. Chaperone-mediated autophagy. Proc. Am. Thorac. Soc. 7:29–39 [Google Scholar]
  11. Birgisdottir AB, Lamark T, Johansen T. 2013. The Lir motif—crucial for selective autophagy. J. Cell Sci. 126:3237–47 [Google Scholar]
  12. Borsello T, Croquelois K, Hornung JP, Clarke PG. 2003. N-methyl-d-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway. Eur. J. Neurosci. 18:473–85 [Google Scholar]
  13. Bowles KR, Brooks SP, Dunnett SB, Jones L. 2012. Gene expression and behaviour in mouse models of HD. Brain Res. Bull. 88:276–84 [Google Scholar]
  14. Broadwell RD, Cataldo AM. 1984. The neuronal endoplasmic reticulum: its cytochemistry and contribution to the endomembrane system. II. Axons and terminals. J. Comp. Neurol. 230:231–48 [Google Scholar]
  15. Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S. et al. 2013. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9:1308–20 [Google Scholar]
  16. Chakrama FZ, Seguin-Py S, Le Grand JN, Fraichard A, Delage-Mourroux R. et al. 2010. GABARAPL1 (GEC1) associates with autophagic vesicles. Autophagy 6:495–505 [Google Scholar]
  17. Cheng HC, Kim SR, Oo TF, Kareva T, Yarygina O. et al. 2011. Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J. Neurosci. 31:2125–35 [Google Scholar]
  18. Chu CT. 2006. Autophagic stress in neuronal injury and disease. J. Neuropathol. Exp. Neurol. 65:423–32 [Google Scholar]
  19. Ciechanover A, Orian A, Schwartz AL. 2000. Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22:442–51 [Google Scholar]
  20. Clausen TH, Lamark T, Isakson P, Finley K, Larsen KB. et al. 2010. p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. Autophagy 6:330–44 [Google Scholar]
  21. Colin E, Zala D, Liot G, Rangone H, Borrell-Pagès M. et al. 2008. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27:2124–34 [Google Scholar]
  22. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ. et al. 2006. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313:324–28 [Google Scholar]
  23. Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. 2012. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab. 15:247–55 [Google Scholar]
  24. Cuervo AM, Knecht E, Terlecky SR, Dice JF. 1995. Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am. J. Physiol. 269:C1200–8 [Google Scholar]
  25. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. 2004. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–95 [Google Scholar]
  26. Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F. et al. 2013. Recessive mutations in Epg5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat. Genet. 45:83–87 [Google Scholar]
  27. Danon MJ, Oh SJ, DiMauro S, Manaligod JR, Eastwood A. et al. 1981. Lysosomal glycogen storage disease with normal acid maltase. Neurology 31:51–57 [Google Scholar]
  28. De Strooper B, Iwatsubo T, Wolfe MS. 2012. Presenilins and γ-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:A006304 [Google Scholar]
  29. De Vries RL, Przedborski S. 2013. Mitophagy and Parkinson's disease: be eaten to stay healthy. Mol. Cell Neurosci. 55:37–43 [Google Scholar]
  30. Dice JF, Terlecky SR, Chiang HL, Olson TS, Isenman LD. et al. 1990. A selective pathway for degradation of cytosolic proteins by lysosomes. Semin. Cell Biol. 1:449–55 [Google Scholar]
  31. Ding WX, Ni HM, Li M, Liao Y, Chen X. et al. 2010. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J. Biol. Chem. 285:27879–90 [Google Scholar]
  32. Dixon JS. 1967. “Phagocytic” lysosomes in chromatolytic neurones. Nature 215:657–58 [Google Scholar]
  33. Dong XX, Wang YR, Qin S, Liang ZQ, Liu BH. et al. 2012. p53 mediates autophagy activation and mitochondria dysfunction in kainic acid-induced excitotoxicity in primary striatal neurons. Neuroscience 207:52–64 [Google Scholar]
  34. Dunn WA Jr. 1990. Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J. Cell Biol. 110:1923–33 [Google Scholar]
  35. Efeyan A, Zoncu R, Sabatini DM. 2012. Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18:524–33 [Google Scholar]
  36. Eskelinen EL, Tanaka Y, Saftig P. 2003. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 13:137–45 [Google Scholar]
  37. Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM. 2008. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155:567–72 [Google Scholar]
  38. Fengsrud M, Erichsen ES, Berg TO, Raiborg C, Seglen PO. 2000. Ultrastructural characterization of the delimiting membranes of isolated autophagosomes and amphisomes by freeze-fracture electron microscopy. Eur. J. Cell Biol. 79:871–82 [Google Scholar]
  39. Filimonenko M, Isakson P, Finley KD, Anderson M, Jeong H. et al. 2010. The selective macroautophagic degradation of aggregated proteins requires the Pi3p-binding protein Alfy. Mol. Cell 38:265–79 [Google Scholar]
  40. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S. et al. 2007. Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–25 [Google Scholar]
  41. Finley KD, Edeen PT, Cumming RC, Mardahl-Dumesnil MD, Taylor BJ. et al. 2003. blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration. J. Neurosci. 23:1254–64 [Google Scholar]
  42. Fortun J, Dunn WA Jr, Joy S, Li J, Notterpek L. 2003. Emerging role for autophagy in the removal of aggresomes in Schwann cells. J. Neurosci. 23:10672–80 [Google Scholar]
  43. Fox JH, Connor T, Chopra V, Dorsey K, Kama JA. et al. 2010. The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease. Mol. Neurodegener. 5:26 [Google Scholar]
  44. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM. et al. 2012. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J. Neurosci. 32:7585–93 [Google Scholar]
  45. Ge L, Melville D, Zhang M, Schekman R. 2013. The ER–Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2:e00947 [Google Scholar]
  46. Geisler S, Holmstrom KM, Treis A, Skujat D, Weber SS. et al. 2010. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6:871–78 [Google Scholar]
  47. Gill A, Kidd J, Vieira F, Thompson K, Perrin S. 2009. No benefit from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial ALS. PLoS ONE 4:E6489 [Google Scholar]
  48. Ginsberg SD, Alldred MJ, Counts SE, Cataldo AM, Neve RL. et al. 2010. Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression. Biol. Psychiatry 68:885–93 [Google Scholar]
  49. Gómez-Suaga P, Fdez E, Blanca Ramírez M, Hilfiker S. 2012. A link between autophagy and the pathophysiology of LRRK2 in Parkinson's disease. Park. Dis. 2012:324521 [Google Scholar]
  50. Goodman MN, Lowell B, Belur E, Ruderman NB. 1984. Sites of protein conservation and loss during starvation: influence of adiposity. Am. J. Physiol. 246:E383–90 [Google Scholar]
  51. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R. et al. 2010. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–67 [Google Scholar]
  52. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A. et al. 2013. Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–93 [Google Scholar]
  53. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y. et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–89 [Google Scholar]
  54. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. 2009. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11:1433–37 [Google Scholar]
  55. Heng MY, Duong DK, Albin RL, Tallaksen-Greene SJ, Hunter JM. et al. 2010. Early autophagic response in a novel knock-in model of Huntington disease. Hum. Mol. Genet. 19:3702–20 [Google Scholar]
  56. Hernandez D, Torres CA, Setlik W, Cebrián C, Mosharov EV. et al. 2012. Regulation of presynaptic neurotransmission by macroautophagy. Neuron 74:277–84 [Google Scholar]
  57. Hirano M, Nakamura Y, Saigoh K, Sakamoto H, Ueno S. et al. 2013. Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. Neurology 80:458–63 [Google Scholar]
  58. Hollenbeck PJ. 1993. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J. Cell Biol. 121:305–15 [Google Scholar]
  59. Holtzman E, Novikoff AB. 1965. Lysomes in the rat sciatic nerve following crush. J. Cell Biol. 27:651–69 [Google Scholar]
  60. Isakson P, Holland P, Simonsen A. 2012. The role of ALFY in selective autophagy. Cell Death Differ. 20:12–20 [Google Scholar]
  61. Itakura E, Kishi-Itakura C, Mizushima N. 2012. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151:1256–69 [Google Scholar]
  62. Janen SB, Chaachouay H, Richter-Landsberg C. 2010. Autophagy is activated by proteasomal inhibition and involved in aggresome clearance in cultured astrocytes. Glia 58:1766–74 [Google Scholar]
  63. Johnson CW, Melia TJ, Yamamoto A. 2012. Modulating macroautophagy: a neuronal perspective. Future Med. Chem. 4:1715–31 [Google Scholar]
  64. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T. et al. 2000. Lc3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19:5720–28 [Google Scholar]
  65. Kaushik S, Cuervo AM. 2012. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22:407–17 [Google Scholar]
  66. Kaushik S, Massey AC, Mizushima N, Cuervo AM. 2008. Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol. Biol. Cell 19:2179–92 [Google Scholar]
  67. Kaushik S, Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S. et al. 2011. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 14:173–83 [Google Scholar]
  68. King MA, Hands S, Hafiz F, Mizushima N, Tolkovsky AM, Wyttenbach A. 2008. Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis. Mol. Pharmacol. 73:1052–63 [Google Scholar]
  69. Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL. et al. 2009. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33:505–16 [Google Scholar]
  70. Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A. et al. 2007. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc. Natl. Acad. Sci. USA 104:11441–46 [Google Scholar]
  71. Koga H, Cuervo AM. 2011. Chaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration. Neurobiol. Dis. 43:29–37 [Google Scholar]
  72. Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M. et al. 2008. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am. J. Pathol. 172:454–69 [Google Scholar]
  73. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J. et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–84 [Google Scholar]
  74. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T. et al. 2007a. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–63 [Google Scholar]
  75. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J. et al. 2007b. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. USA 104:14489–94 [Google Scholar]
  76. Korac J, Schaeffer V, Kovacevic I, Clement AM, Jungblut B. et al. 2013. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J. Cell Sci. 126:580–92 [Google Scholar]
  77. Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM. et al. 2012. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron 74:1031–44 [Google Scholar]
  78. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H. et al. 2004. The role of autophagy during the early neonatal starvation period. Nature 432:1032–36 [Google Scholar]
  79. Landles C, Sathasivam K, Weiss A, Woodman B, Moffitt H. et al. 2010. Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease. J. Biol. Chem. 285:8808–23 [Google Scholar]
  80. Larsen KE, Fon EA, Hastings TG, Edwards RH, Sulzer D. 2002. Methamphetamine-induced degeneration of dopaminergic neurons involves autophagy and upregulation of dopamine synthesis. J. Neurosci. 22:8951–60 [Google Scholar]
  81. Lee JA, Gao FB. 2008. ESCRT, autophagy, and frontotemporal dementia. BMB Rep. 41:827–32 [Google Scholar]
  82. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS. et al. 2010a. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141:1146–58 [Google Scholar]
  83. Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E. et al. 2010b. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 29:969–80 [Google Scholar]
  84. Leil TA, Chen ZW, Chang CS, Olsen RW. 2004. GABAA receptor-associated protein traffics GABAA receptors to the plasma membrane in neurons. J. Neurosci. 24:11429–38 [Google Scholar]
  85. Li L, Zhang X, Le W. 2008. Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 4:290–93 [Google Scholar]
  86. Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ. 2005. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J. 272:4211–20 [Google Scholar]
  87. Liang CC, Wang C, Peng X, Gan B, Guan JL. 2010. Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J. Biol. Chem. 285:3499–509 [Google Scholar]
  88. Lim A, Kraut R. 2009. The Drosophila BEACH family protein, Blue Cheese, links lysosomal axon transport with motor neuron degeneration. J. Neurosci. 29:951–63 [Google Scholar]
  89. Liot G, Zala D, Pla P, Mottet G, Piel M, Saudou F. 2013. Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J. Neurosci. 33:6298–309 [Google Scholar]
  90. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF. et al. 2010. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 107:14164–69 [Google Scholar]
  91. Maday S, Wallace KE, Holzbaur EL. 2012. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J. Cell Biol. 196:407–17 [Google Scholar]
  92. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A. et al. 1996. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506 [Google Scholar]
  93. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J. et al. 2008. Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J. Clin. Investig. 118:777–88 [Google Scholar]
  94. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H. et al. 2010. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13:567–76 [Google Scholar]
  95. Maruyama H, Morino H, Ito H, Izumi Y, Kato H. et al. 2010. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–26 [Google Scholar]
  96. Matthews MR, Raisman G. 1972. A light and electron microscopic study of the cellular response to axonal injury in the superior cervical ganglion of the rat. Proc. R. Soc. Lond. B 181:43–79 [Google Scholar]
  97. McMahon J, Huang X, Yang J, Komatsu M, Yue Z. et al. 2012. Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J. Neurosci. 32:15704–14 [Google Scholar]
  98. Mijaljica D, Prescott M, Devenish RJ. 2011. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy 7:673–82 [Google Scholar]
  99. Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, Okamoto K. 2006. Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 249:13–18 [Google Scholar]
  100. Mizushima N, Levine B. 2010. Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12:823–30 [Google Scholar]
  101. 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 15:1101–11 [Google Scholar]
  102. Mizushima N, Yoshimori T, Ohsumi Y. 2011. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27:107–32 [Google Scholar]
  103. Mohseni S. 2011. Autophagy in insulin-induced hypoglycaemic neuropathy. Pathology 43:254–60 [Google Scholar]
  104. Moreau K, Ravikumar B, Renna M, Puri C, Rubinsztein DC. 2011. Autophagosome precursor maturation requires homotypic fusion. Cell 146:303–17 [Google Scholar]
  105. Mortimore GE, Pösö AR, Lardeux BR. 1989. Mechanism and regulation of protein degradation in liver. Diabetes Metab. Rev. 5:49–70 [Google Scholar]
  106. Nair U, Jotwani A, Geng J, Gammoh N, Richerson D. et al. 2011. SNARE proteins are required for macroautophagy. Cell 146:290–302 [Google Scholar]
  107. Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. 2010. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6:1090–106 [Google Scholar]
  108. Narendra D, Walker JE, Youle R. 2012. Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb. Perspect. Biol. 4:a011338 [Google Scholar]
  109. Neely KM, Green KN, Laferla FM. 2011. Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a γ-secretase-independent manner. J. Neurosci. 31:2781–91 [Google Scholar]
  110. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B. et al. 2010. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66–79 [Google Scholar]
  111. Nezis IP, Simonsen A, Sagona AP, Finley K, Gaumer S. et al. 2008. Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J. Cell Biol. 180:1065–71 [Google Scholar]
  112. Nishimura T, Kaizuka T, Cadwell K, Sahani MH, Saitoh T. et al. 2013. Fip200 regulates targeting of Atg16l1 to the isolation membrane. EMBO Rep. 14:284–91 [Google Scholar]
  113. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S. et al. 2000. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:906–10 [Google Scholar]
  114. Nixon RA, Cataldo AM. 2006. Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J. Alzheimers Dis. 9:277–89 [Google Scholar]
  115. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C. et al. 2005. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64:113–22 [Google Scholar]
  116. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P. et al. 2010. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11:45–51 [Google Scholar]
  117. Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H. et al. 2013. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16:394–406 [Google Scholar]
  118. Osawa T, Mizuno Y, Fujita Y, Takatama M, Nakazato Y, Okamoto K. 2011. Optineurin in neurodegenerative diseases. Neuropathology 31:569–74 [Google Scholar]
  119. Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A. et al. 2012. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am. J. Hum. Genet. 91:1065–72 [Google Scholar]
  120. Perez FA, Palmiter RD. 2005. Parkin-deficient mice are not a robust model of parkinsonism. Proc. Natl. Acad. Sci. USA 102:2174–79 [Google Scholar]
  121. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R. et al. 2008. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J. Clin. Investig. 118:2190–99 [Google Scholar]
  122. Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C. et al. 2009. Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph. Lateral Scler. 10:221–28 [Google Scholar]
  123. Proenca CC, Stoehr N, Bernhard M, Seger S, Genoud C. et al. 2013. Atg4b-dependent autophagic flux alleviates Huntington's disease progression. PLoS ONE 8:E68357 [Google Scholar]
  124. Pryor PR, Mullock BM, Bright NA, Lindsay MR, Gray SR. et al. 2004. Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events. EMBO Rep. 5:590–95 [Google Scholar]
  125. Punnonen EL, Pihakaski K, Mattila K, Lounatmaa K, Hirsimäki P. 1989. Intramembrane particles and filipin labelling on the membranes of autophagic vacuoles and lysosomes in mouse liver. Cell Tissue Res. 258:269–76 [Google Scholar]
  126. Rangaraju S, Verrier JD, Madorsky I, Nicks J, Dunn WA Jr, Notterpek L. 2010. Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice. J. Neurosci. 30:11388–97 [Google Scholar]
  127. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. 2010. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12:747–57 [Google Scholar]
  128. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S. et al. 2004. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36:585–95 [Google Scholar]
  129. Régulier E, Trottier Y, Perrin V, Aebischer P, Déglon N. 2003. Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum. Hum. Mol. Genet. 12:2827–36 [Google Scholar]
  130. Renna M, Schaffner C, Winslow AR, Menzies FM, Peden AA. et al. 2011. Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. J. Cell Sci. 124:469–82 [Google Scholar]
  131. Robberecht W, Philips T. 2013. The changing scene of amyotrophic lateral sclerosis. Nat. Rev. Neurosci. 14:248–64 [Google Scholar]
  132. Roberts VJ, Gorenstein C. 1987. Examination of the transient distribution of lysosomes in neurons of developing rat brains. Dev. Neurosci. 9:255–64 [Google Scholar]
  133. Rodríguez-Muela N, Germain F, Mariño G, Fitze PS, Boya P. 2012. Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. Cell Death Differ. 19:162–69 [Google Scholar]
  134. Rusten TE, Filimonenko M, Rodahl LM, Stenmark H, Simonsen A. 2008. ESCRTing autophagic clearance of aggregating proteins. Autophagy 4:233–36 [Google Scholar]
  135. Sah DW, Aronin N. 2011. Oligonucleotide therapeutic approaches for Huntington disease. J. Clin. Investig. 121:500–7 [Google Scholar]
  136. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B. et al. 2011. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell 20:131–39 [Google Scholar]
  137. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. 2007. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J. Biol. Chem. 282:5641–52 [Google Scholar]
  138. Schwarz L, Goldbaum O, Bergmann M, Probst-Cousin S, Richter-Landsberg C. 2012. Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J. Mol. Neurosci. 47:256–66 [Google Scholar]
  139. Schweers RL, Zhang J, Randall MS, Loyd MR, Li W. et al. 2007. Nix is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl. Acad. Sci. USA 104:19500–5 [Google Scholar]
  140. Seglen PO, Bohley P. 1992. Autophagy and other vacuolar protein degradation mechanisms. Experientia 48:158–72 [Google Scholar]
  141. Shehata M, Matsumura H, Okubo-Suzuki R, Ohkawa N, Inokuchi K. 2012. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci. 32:10413–22 [Google Scholar]
  142. Shen W, Ganetzky B. 2009. Autophagy promotes synapse development in Drosophila. J. Cell Biol. 187:71–79 [Google Scholar]
  143. Shimizu H, Toyoshima Y, Shiga A, Yokoseki A, Arakawa K. et al. 2013. Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene. Acta Neuropathol. 126:453–59 [Google Scholar]
  144. Shin J-H, Ko HS, Kang H, Lee Y, Lee Y-I. et al. 2011. PARIS (ZNF746) repression of PGC-1a contributes to neurodegeneration in Parkinson's disease. Cell 144:689–702 [Google Scholar]
  145. Smith CM, Mayer JA, Duncan ID. 2013. Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant. J. Neurosci. 33:8088–100 [Google Scholar]
  146. Song JW, Misgeld T, Kang H, Knecht S, Lu J. et al. 2008. Lysosomal activity associated with developmental axon pruning. J. Neurosci. 28:8993–9001 [Google Scholar]
  147. Steele JW, Ju S, Lachenmayer ML, Liken J, Stock A. et al. 2013a. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol. Psychiatry 18:882–88 [Google Scholar]
  148. Steele JW, Lachenmayer ML, Ju S, Stock A, Liken J. et al. 2013b. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol. Psychiatry 18:889–97 [Google Scholar]
  149. Sugie K, Yamamoto A, Murayama K, Oh SJ, Takahashi M. et al. 2002. Clinicopathological features of genetically confirmed Danon disease. Neurology 58:1773–78 [Google Scholar]
  150. Takáts S, Nagy P, Varga Á, Pircs K, Kárpáti M. et al. 2013. Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. J. Cell Biol. 201:531–39 [Google Scholar]
  151. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y. 1992. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol. 119:301–11 [Google Scholar]
  152. Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D. et al. 2000. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–6 [Google Scholar]
  153. Tang G, Yue Z, Talloczy Z, Hagemann T, Cho W. et al. 2008. Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways. Hum. Mol. Genet. 17:1540–55 [Google Scholar]
  154. Tanik SA, Schultheiss CE, Volpicelli-Daley LA, Brunden KR, Lee VM. 2013. Lewy body-like α-synuclein aggregates resist degradation and impair macroautophagy. J. Biol. Chem. 288:15194–210 [Google Scholar]
  155. Thomas M, Alegre-Abarrategui J, Wade-Martins R. 2013. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain 136:1345–60 [Google Scholar]
  156. Tian F, Morimoto N, Liu W, Ohta Y, Deguchi K. et al. 2011. In vivo optical imaging of motor neuron autophagy in a mouse model of amyotrophic lateral sclerosis. Autophagy 7:985–92 [Google Scholar]
  157. Tsvetkov AS, Miller J, Arrasate M, Wong JS, Pleiss MA, Finkbeiner S. 2010. A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc. Natl. Acad. Sci. USA 107:16982–87 [Google Scholar]
  158. Umekawa M, Klionsky DJ. 2012. The cytoplasm-to-vacuole targeting pathway: a historical perspective. Int. J. Cell Biol. 2012:142634 [Google Scholar]
  159. Vantaggiato C, Crimella C, Airoldi G, Polishchuk R, Bonato S. et al. 2013. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain 136:3119–39 [Google Scholar]
  160. Vingtdeux V, Chandakkar P, Zhao H, d'Abramo C, Davies P, Marambaud P. 2011. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. FASEB J. 25:219–31 [Google Scholar]
  161. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. 2008. Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283:23542–56 [Google Scholar]
  162. Wagenmakers AJ, Schepens JT, Veerkamp JH. 1984. Increase of the activity state and loss of total activity of the branched-chain 2-oxo acid dehydrogenase in rat diaphragm during incubation. Biochem. J. 224:491–96 [Google Scholar]
  163. Wang C, Liang C-C, Bian ZC, Zhu Y, Guan J-L. 2013. FIP200 is required for maintenance and differentiation of postnatal neural stem cells. Nat. Neurosci. 16:532–42 [Google Scholar]
  164. Wang H, Bedford FK, Brandon NJ, Moss SJ, Olsen RW. 1999. GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton. Nature 397:69–72 [Google Scholar]
  165. Wang JT, Medress ZA, Barres BA. 2012. Axon degeneration: molecular mechanisms of a self-destruction pathway. J. Cell Biol. 196:7–18 [Google Scholar]
  166. Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E. et al. 2009. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18:4153–70 [Google Scholar]
  167. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S. et al. 2004. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36:377–81 [Google Scholar]
  168. Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z. 2010. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J. 29:1792–802 [Google Scholar]
  169. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE. et al. 2010. α-Synuclein impairs macroautophagy: implications for Parkinson's disease. J. Cell Biol. 190:1023–37 [Google Scholar]
  170. Wong YC, Holzbaur EL. 2014. The regulation of autophagosome dynamics by Huntingtin and HAP1 is disrupted by expression of mutant Huntingtin, leading to defective cargo degradation. J. Neurosci. 34:41293–305 [Google Scholar]
  171. Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J. et al. 2008. Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J. Biol. Chem. 283:6783–89 [Google Scholar]
  172. Yamamoto A, Lucas JJ, Hen R. 2000. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101:57–66 [Google Scholar]
  173. Yamamoto A, Simonsen A. 2011. The elimination of accumulated and aggregated proteins: a role for aggrephagy in neurodegeneration. Neurobiol. Dis. 43:17–28 [Google Scholar]
  174. Yang Y, Coleman M, Zhang L, Zheng X, Yue Z. 2013. Autophagy in axonal and dendritic degeneration. Trends Neurosci. 36:418–28 [Google Scholar]
  175. Yang Z, Klionsky DJ. 2010. Eaten alive: a history of macroautophagy. Nat. Cell Biol. 12:814–22 [Google Scholar]
  176. Ylä-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. 2009. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5:1180–85 [Google Scholar]
  177. Young JE, Martinez RA, La Spada AR. 2009. Nutrient deprivation induces neuronal autophagy and implicates reduced insulin signaling in neuroprotective autophagy activation. J. Biol. Chem. 284:2363–73 [Google Scholar]
  178. Yue Z, Friedman L, Komatsu M, Tanaka K. 2009. The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. Biochim. Biophys. Acta 1793:1496–507 [Google Scholar]
  179. Yue Z, Horton A, Bravin M, 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 35:921–33 [Google Scholar]
  180. Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R. et al. 2012. A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J. Neurosci. 32:8633–48 [Google Scholar]
  181. Zhang X, Li L, Chen S, Yang D, Wang Y. et al. 2011. Rapamycin treatment augments motor neuron degeneration in SOD1(G93a) mouse model of amyotrophic lateral sclerosis. Autophagy 7:412–25 [Google Scholar]
  182. Zhao YG, Zhao H, Sun H, Zhang H. 2013. Role of Epg5 in selective neurodegeneration and Vici syndrome. Autophagy 9:1258–62 [Google Scholar]
  183. Zheng S, Clabough EB, Sarkar S, Futter M, Rubinsztein DC, Zeitlin SO. 2010. Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet. 6:E1000838 [Google Scholar]
  184. Zschocke J, Zimmermann N, Berning B, Ganal V, Holsboer F, Rein T. 2011. Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons—dissociation from cholesterol homeostasis. Neuropsychopharmacology 36:1754–68 [Google Scholar]
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