Compromised autophagy and neurodegenerative diseases

Nature Reviews Neuroscience

Volumn 16, Issue 6, 2015, Pages 345-357

  Menzies, Fiona M ^a   Fleming, Angeleen ^a,b   Rubinsztein, David C ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BECLIN 1;

AUTOPHAGOSOME; AUTOPHAGY; CELL MIGRATION; DEGENERATIVE DISEASE; DEGRADATION; GENE MUTATION; HUMAN; LYSOSOME; NERVE DEGENERATION; NEUROMODULATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN INTERACTION; REVIEW; ANIMAL; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; AUTOPHAGY; HUMANS; NEURODEGENERATIVE DISEASES;

EID: 84929903016     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn3961     Document Type: Review

References (189)

1. Imarisio, S. et al. Huntington's disease: from pathology and genetics to potential therapies. Biochem. J. 412, 191-209 (2008).
2. Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780-786 (2006).
3. Tsvetkov, A. S. et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nature Chem. Biol. 9, 586-592 (2013).
4. Hara, T. et al. Suppre ssion of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889 (2006).
5. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegenerati on in mice. Nature 441, 880-884 (2006). References 4 and 5 were the first to demonstrate the importance of autophagy for neuronal health (knockout of Atg5 or Atg7 in neurons resulted in a neurodegenerative phenotype in mice).
6. Kim I.,Lemasters J. J Mitophagy selectively degrades individual damaged mitochondria after photoirradiation Antioxid. Redox Signal. 14 1919-1928 2011).
7. Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell. Biol. 25, 1025-1040 (2005).
8. Ravikumar, B., Berger, Z., Vacher, C., O'Kane, C. J. & Rubinsztein, D. C. Rapamycin pre-treatme nt protects against apoptosis. Hum. Mol. Genet. 15, 1209-1216 (2006).
9. Korolchuk, V. I., Mansilla, A., Menzies, F. M. & Rubinsztein, D. C. Autophagy inhibition compromises degradation of ubiquitin-proteaso me pathway substrates. Mol. Cell 33, 517-527 (2009).
10. Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169-174 (1993).
11. Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075 (2008).
12. Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C. & Rubinsztein, D. C. Plasma membrane contributes to the formation of pre-Autophagosomal structures. Nature Cell Biol. 12, 747-757 (2010).
13. Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nature Cell Biol. 11, 1433-1437 (2009).
14. Yla-Anttila, P., Vihinen, H., Jokitalo, E. & Eskelinen, E. L. 3D tomography revea ls connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180-1185 (2009).
15. van der Vaart, A., Griffith, J. & Reggiori, F. Exit from the Golgi is required for the expansio n of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol. Biol. Cell 21, 2270-2284 (2010).
16. Yen, W. L. et al. The conserved oligomeric Golgi complex is involved in double-membrane v esicle formation during autophagy. J. Cell Biol. 188, 101-114 (2010).
17. Hailey, D. W. et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656-667 (2010).
18. Puri, C., Renna, M., Bento, C. F., Moreau, K. & Rubinsztein, D. C. Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 154, 1285-1299 (2013).
19. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720-5728 (2000).
20. R avikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nature Genet. 37, 771-776 (2005).
21. Moreau, K., Ravikumar, B., Renna, M., Puri, C. & Ru binsztein, D. C. Autophagosome precursor maturation requires homotypic fusion. Cell 146, 303-317 (2011).
22. Fader, C. M., Sanchez, D. G., Mestre, M. B. & Colombo, M. I. TI-VAMP/V AMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim. Biophys. Acta 1793, 1901-1916 (2009).
23. Furuta, N. & Amano, A. Cellula r machinery to fuse antimicrobial autophagosome with lysosome. Commun. Integr. Biol. 3, 385-387 (2010).
24. Alers, S., Loffler, A. S., Wesselborg, S. & Stork, B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 32, 2-11 (2012).
25. Fullgrabe, J., Klionsky, D. J. & Joseph, B. The return of the nucleus: transcriptional and epigenetic control of autophagy. Nature Rev. Mol. Cell Biol. 15, 65-74 (2014).
26. Morselli, E. et al. p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200. Cell Cycle 10, 2763-2769 (2011).
27. Russell, R. C. et al. ULK1 induces a utophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature Cell Biol. 15, 741-750 (2013).
28. Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formatio n, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 55, 238-252 (2014).
29. Mack, H. I., Zheng, B., Asara, J. M. & Thomas, S. M. AMPK-dependent phosphorylation of ULK1 regu lates ATG9 localization. Autophagy 8, 1197-1214 (2012).
30. Papinski, D. et al. Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Mol. Cell 53, 471-483 (2014).
31. Vicinanza, M. et al. PI(5)P regulates autophagosome biogenesis. Mol. Cell 57, 219-234 (2015).
32. Stolz, A., Ernst, A. & Dikic, I.Cargo recognition and trafficking in selective autophagy. Nature Cell Biol. 16, 495-501 (2014).
33. Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protec tive effect on huntingtin-induced cell death. J. Cell Biol. 171, 603-614 (2005).
34. Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505-516 (2009).
35. Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131-24145 (2007).
36. Rogov, V., Dotsch, V., Johansen, T. & Kirkin, V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell 53, 167-178 (2014).
37. Simonsen, A. et al. Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J. Cell Sci. 117, 4239-4251 (2004).
38. Filimonenko, M. et al. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol. Cell 38, 265-279 (2010).
39. Clausen, T. H. et al. p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. Autophagy 6, 330-344 (2010).
40. Novak, I. et al. Nix is a selective au tophagy receptor for mitochondrial clearance. EMBO Rep. 11, 45-51 (2010).
41. Schwarten, M. et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autopha gy 5, 690-698 (2009).
42. Shen, H. M. & Mizushima, N. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends Biochem. Sci. 39, 61-71 (2014).
43. Wong, Y. C. & Holzbaur, E. L. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 34, 1293-1305 (2014).
44. Moreau, K., Renna, M. & Rubinsztein, D. C. Connections between SNAREs and autophagy. Trends Biochem. Sci. 38, 57-63 (2013).
45. Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942-946 (2010).
46. Sardiello, M. et al. A gene network regulating lysosomal biogenesi s and function. Science 325, 473-477 (2009).
47. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433 (2011).
48. F rake, R. A., Ricketts, T., Menzies, F. M. & Rubinsztein, D. C. Autophagy and neurodegeneration. J. Clin. Invest. 125, 65-75 (2015).
49. Haack, T. B., Hogarth, P., Gregory, A., Prokisch, H. & Hayflick, S. J. BPAN: the only X-linked dominant NBIA disorder. Int. Rev. Neurobiol. 110, 85-90 (2013).
50. Saitsu, H. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nature Genet. 45, 445-449 (2013).
51. Orsi, A. et al. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol. Biol. Cell 23, 1860-1873 (2012).
52. Metzger, S. et al. Age at onset in Huntington's disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum. Genet. 128, 453-459 (2010).
53. Met zger, S. et al. The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLoS ONE 8, e68951 (2013).
54. Yan, J. Q. et al. Over expression of human E46K mutant ?-synuclein impairs macroautophagy via inactivation of JNK1-Bcl-2 pathway. Mol. Neurobiol. 50, 685-701 (2014).
55. Subramaniam, S., Sixt, K. M., Barrow, R. & Snyd er, S. H. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327-1330 (2009).
56. Mealer, R. G., Murray, A. J., Shahani, N., Subramaniam, S. & Snyde r, S. H. Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J. Biol. Chem. 289, 3547-3554 (2014). The results from this paper suggest a possible mechanism for the selecti ve vulnerability of striatal cells in HD.
57. Sagona, A. P. et al. A tumor-Associated mutation of FYVE-CENT prevents its interaction with Beclin 1 and interferes with cytokinesis. PLoS ONE 6, e17086 (2011).
58. Vantaggiato, C. et al. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain 136, 3119-3139 (2013).
59. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genet. 41, 1088-1093 (2009).
60. Jun, G. et al. Meta-Analysis confirms CR1, C LU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch. Neurol. 67, 1473-1484 (2010).
61. Ando, K. et al. Clathrin adaptor CALM/PICALM is associated with neuro fibrillary tangles and is cleaved in Alzheimer's brains. Acta Neuropathol. 125, 861-878 (2013).
62. Moreau, K. et al. PICALM modulates autophagy activity and tau accumulation. Nature Commun. 5, 4998 (2014).
63. Szatmari, Z. & Sass, M. The autophagic roles of Rab small GTPases and their upstream regulators: a review. Autophagy 10, 1154-1166 (2014).
64. Verhoeven K.,et al Mutations in the small GTP-Ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72 722-727 2003).
65. Yang, Y. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nature Genet. 29, 160-165 (2001).
66. Topp, J. D., Gray, N. W., Gerard, R. D. & Horazdovsky, B. F. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J. Biol. Chem. 279, 24612-24623 (2004).
67. Ravikumar, B., Imarisio, S., Sarkar, S., O'Kane, C. J. & Rubinsztein, D. C. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J. Cell Sci. 121, 1649-1660 (2008).
68. Otomo, A., Kunita, R., Suzuki-Utsunomiya, K., Ikeda, J. E. & Hadano, S. Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of th eir cellular function and leads to disturbed amphisome formation. FEBS Lett. 585, 730-736 (2011).
69. Levine, T. P., Daniels, R. D., Gatta, A. T., Wong, L. H. & Hayes, M. J. The pr oduct of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29, 499-503 (2013).
70. Farg, M. A. et al. C9ORF72, implicated in amytro phic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum. Mol. Genet. 23, 3579-3595 (2014).
71. Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345,1192-1194 (2014).
72. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat ure Genet. 37, 806-808 (2005).
73. Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G. & Gao, F. B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561-1567 (2007).
74. Seaman, M. N. The retromer complex-endosomal protein recycling and beyond. J. Cell Sci. 125, 4693-4702 (2012).
75. Zavodszky, E. et al. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy. Nature Commun. 5, 3828 (2014).
76. Zimprich, A. et al. A mutation in VP S35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168-175 (2011).
77. Winslow, A. R. et al. ?-synuclein impairs macroautophagy: implications f or Parkinson's disease. J. Cell Biol. 190, 1023-1037 (2010).
78. Singleton, A. B. et al. ?-synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).
79. Cooper, A. A. et al. ?-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313, 324-328 (2006).
80. Freeman, C., Seaman, M. N. & Reid, E. The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function. Biochim. Biophys. Acta 1832, 160-173 (2013).
81. Ropers, F. et al. Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP. Hum. Mol. Genet. 20, 2585-2590 (2011).
82. Vilarino-Guell, C. et al. DNAJC13 mutations in Parkinson disease. Hum. Mol. Genet. 23, 1794-1801 (2014).
83. Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann. Neurol. 70, 913-919 (2011).
84. Luty, A. A. et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann. Neurol. 68, 639-649 (2010).
85. Prause, J. et al. Altered localization, abnormal modification and loss of function of Sigm a receptor-1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 22, 1581-1600 (2013).
86. Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L. & Ruoho, A. E. The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. Neuroscience 167, 247-255 (2010).
87. Mancuso, R. et al. Sigma-1R agonist imp roves motor function and motoneuron survival in ALS mice. Neurotherapeutics 9, 814-826 (2012).
88. Vollrath, J. T. et al. Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances. Cell Death Dis. 5, e1290 (2014).
89. Lieberman, A. P. et al. Autophagy in lysosomal storage disorders. Autophagy 8, 719-730 (2012).
90. Swan, M. & Saunders-Pullman, R. The association between ?-glucocerebrosidase mutations and parkinsonism. Curr. Neurol. Neurosci. Rep. 13, 368 (2013).
91. Osellame, L. D. et al. Mitochondria and quality control defects in a mouse model of Gaucher disease-links to Parkinson's disease. Cell. Metabolism 17, 941-953 (2013).
92. Mazzulli, J. R. et al. Gaucher d isease glucocerebrosidase and ?-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37-52 (2011).
93. Murphy, K. E. et al. Reduced glucocerebrosidase is associated with increased ?-synuclein in sporadic Parkinson's disease. Brain 137, 834-848 (2014).
94. Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434-6451 (2008).
95. Gabande-Rodriguez, E., Boya, P., Labrador, V., Dotti, C. G.& Ledesma, M. D. High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A. Cell Death Differ. 21, 864-875 (2014).
96. Ramirez, A. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nature Genet. 38, 1184-1191 (2006).
97. Dehay, B. et al. Loss of P-type ATPase AT P13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl Acad. Sci. USA 109, 9611-9616 (2012).
98. Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146-1158 (2010).
99. Avrahami, L. et al. Inhibition of glycogen synthase kinase-3 ameliorates ?-Amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J. Biol. Chem. 288, 1295-1306 (2013).
100. Zhang, X. et al. A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J. Neurosci. 32, 8633-8648 (2012).
101. Coe n, K. et al. Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J. Cell Biol. 198, 23-35 (2012).
102. Wilson, C. A. et al.Degradative organelles containing mislocalized ?-And ?-synuclein proliferate in presenilin-1 null neurons. J. Cell Biol. 165, 335-346 (2004).
103. Neely, K. M., Green, K. N. & LaFerla, F. M. Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a ?-secretase-independent manner. J. Neurosci. 31, 2781-2791 (2011).
104. Cortes, C. J. et al. Polyglu tamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nature Neurosci. 17, 1180-1189 (2014).
105. Decressac, M. et al. TFEB-mediated autophagy rescues midbrai n dopamine neurons from ?-synuclein toxicity. Proc. Natl Acad. Sci. USA 110, E1817-E1826 (2013).
106. Lee, J. K. et al. Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis i n Alzheimer's disease. J. Exp. Med. 211, 1551-1570 (2014).
107. Chang, J., Lee, S. & Blackstone, C. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J. Clin. Invest. 124, 5249-5262 (2014).
108. Zatloukal, K. et al. p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. Am. J. Pathol. 160, 255-263 (2002).
109. Mori, F. et al. Optineurin immu noreactivity in neuronal nuclear inclusions of polyglutamine diseases (Huntington's, DRPLA, SCA2, SCA3) and intranuclear inclusion body disease. Acta Neuropathol. 123, 747-749 (2012).
110. Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223-226 (2010).
111. Saitoh, Y. et al. p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies. J. Biol. Chem. 290, 1442-1453 (2015).
112. Doi, H. et al. p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inc lusion formation in a spinal and bulbar muscular atrophy mouse model. J. Neurosci. 33, 7710-7727 (2013).
113. Kurosawa, M. et al. Depletion of p62 reduces nuclear inclusions and paradoxically amel iorates disease phenotypes in Huntington's model mice. Hum. Mol. Genet. 24, 1092-1105 (2014).
114. Lu, K., Psakhye, I. & Jentsch, S. Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family. Cell 158, 549-563 (2014).
115. Watanabe, Y. & Tanaka, M. p62/SQSTM1 in autophagic clearance of a non-ubiquitylated substrate. J. Cell Sci. 124, 2692-2701 (2011).
116. Thurston, T. L., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nature Immunol. 10, 1215-1221 (2009).
117. Jo, C. et al. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nature Commun. 5, 3496 (2014).
118. Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nature Neurosci. 13, 567-576 (2010).
119. Rui, Y. N. et al. Huntingtin functions as a scaffold for selective macroautophagy. Nature Cell Biol. 17, 262-275 (2015).
120. Fecto, F. et al. SQSTM1 mutations in familial and spora dic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440-1446 (2011).
121. Teyssou, E. et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol. 125, 511-522 (2013).
122. Wong, Y. C. & Holzbaur, E. L. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc. Natl Acad. Sci. USA 111, E4439-E4448 ( 2014).
123. Harris, H. & Rubinsztein, D. C. Control of autophagy as a therapy for neurodegenerative disease. Nature Rev. Neurol. 8, 108-117 (2012).
124. Rodriguez-Muela, N., Germain, F., Marino, G., Fitze, P. S. & Boya, P. Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. Cell Death Differ. 19, 162-169 (2012).
125. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585-595 (2 004). Using rapamycin to treat animal models of HD, this study was the first to demonstrate that upregulation of autophagy can have a beneficial effect in in vivo models of the disease.
126. Menzies, F. M. et al. Autophagy i nduction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133, 93-104 (2010).
127. Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-? levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979 (2010).
128. Jiang, T. et al. Temsirolimus promotes autophagic clearance of amyloid-? and provides p rotective effects in cellular and animal models of Alzheimer's disease. Pharmacol. Res. 81, 54-63 (2014).
129. Williams, A. et al. Novel targets for Huntington's disease in an mTOR-independent autophag y pathway. Nature Chem. Biol. 4, 295-305 (2008).
130. Rose, C. et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease. Hum. Mol. Genet. 19, 2144-2153 (2010).
131. Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101-1111 (2005).
132. Shimada, K. et al. Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion. Neurobiol. Dis. 46, 101-108 (2012).
133. Li, L. et al. Autophagy enhance r carbamazepine alleviates memory deficits and cerebral amyloid-? pathology in a mouse model of Alzheimer's disease. Curr. Alzheimer Res. 10, 433-441 (2013).
134. Menzies, F. M. et al. Calpain inhibiti on mediates autophagy-dependent protection against polyglutamine toxicity. Cell Death Differ. 22, 433-444 (2014).
135. Sarkar, S., Davies, J. E., Huang, Z., Tunnacliffe, A. & Rubinsztei n, D. C. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and ?-synuclein. J. Biol. Chem. 282, 5641-5652 (2007).
136. Rodriguez-Navarro, J. A. et al. Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol. Dis. 39, 423-438 (2010).
137. Schaeffer V.,et al. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy Brain 135, 2169-2177, 2012
138. Castillo, K. et al. Trehal ose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9, 1308-1320 (2013).
139. Zhang, X. et al. MTOR-independent, autophagic enhancer trehal ose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis. Autophagy 10, 588-602 (2014).
140. Medina, D. L. et al. Transcripti onal activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21, 421-430 (2011).
141. Polito, V. A. et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicit y by transcription factor EB. EMBO Mol. Med. 6, 1142-1160 (2014).
142. Yang, D. S. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258-277 (2011).
143. Castillo, K. et al. Measurement of autophagy flux in the nervous system in vivo. Cell Death Dis. 4, e917 (2013).
144. Liu J.,et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13 Cell 147, 223-234, 2011).
145. Lucin, K. M. et al. Mi croglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron 79, 873-886 (2013).
146. Clark, I. E. et al. Drosophila pink1 is required for mitoc hondrial function and interacts genetically with parkin. Nature 441, 1162-1166 (2006).
147. Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157-1161 (2006).
148. Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795-803 (2008).
149. Becker, D., Richter, J., Tocilescu, M. A., Przedborski, S. & Voos, W. Pink1 kinase and its membrane potential (Deltapsi)-dependent cleavage product both localize to outer mitochondrial membrane by unique targe ting mode. J. Biol. Chem. 287, 22969-22987 (2012).
150. Greene, A. W. et al. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 13, 378-385 (2012).
151. Jin, S. M. et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933-942 (2010).
152. Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dep endent on VDAC1 and p62/SQSTM1. Nature Cell Biol. 12, 119-131 (2010).
153. Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211-221 (2010).
154. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1 000298 (2010).
155. Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378-383 (2010).
156. de Vries , R. L. & Przedborski, S. Mitophagy and Parkinson's disease: be eaten to stay healthy. Mol. Cell. Neurosci. 55, 37-43 (2013).
157. Bingol, B. et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370-375 (2014).
158. Narendra, D., Kane, L. A., Hauser, D. N., Fearnley, I. M. & Youle, R. J. p62/SQSTM1 is required for Parkin-induc ed mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6, 1090-1106 (2010).
159. Scarffe, L. A., Stevens, D. A., Dawson, V. L. & Dawson, T. M. Parkin and PINK1 : much more than mitophagy. Trends Neurosci. 37, 315-324 (2014).
160. Ashrafi, G., Schlehe, J. S., LaVoie, M. J. & Schwarz, T. L. Mitophagy of damaged mitochondria occurs locally in distal neuro nal axons and requires PINK1 and Parkin. J. Cell Biol. 206, 655-670 (2014).
161. Chu, C. T. et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nature Cell Biol. 15, 1197-1205 (2013).
162. Do, C. B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component fo r Parkinson's disease. PLoS Genet. 7, e1002141 (2011).
163. Ivatt, R. M. et al. Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc. Natl Acad. Sci. USA 111, 8494-8499 (2014).
164. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882-896 (2014).
165. Cuervo, A. M. & Wong, E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 24, 92-104 (2014).
166. Wang, G. & Mao, Z. Chaperone-mediated aut ophagy: roles in neurodegeneration. Transl. Neurodegener. 3, 20 (2014).
167. Xilouri, M. & Stefanis, L. Chaperone mediated autophagy to the rescue: a new-fangled target for the treatment of neurodegenera tive diseases. Mol. Cell. Neurosci. http://dx.doi.org/10.1016/j.mcn.2015.01.003 (2015).
168. Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant ?-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295 (2004).
169. Orenstein, S. J. et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nature Neurosci. 16, 394-406 (2013).
170. Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153-4170 (2009).
171. Pacheco, C. D. & Lieberman, A. P. The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev. Mol. Med. 10, e26 (2008).
172. Ko, D. C. et al. Cell-Autonomous death of cerebellar Purkinje neurons with autophagy in Niemann-Pick type C disease. PLoS Genet. 1, 81-95 (2005).
173. Kimura, S., Noda, T. & Yoshimori, T. Dissection of the autophagosome maturation process by a novel report er protein, tandem fluorescent-tagged LC3. Autophagy 3, 452-460 (2007).
174. Elrick, M. J., Yu, T., Chung, C. & Lieberman, A. P. Impaired proteolysis underlies autophagic dysfunction in Niema nn-Pick type C disease. Hum. Mol. Genet. 21, 4876-4887 (2012).
175. Ordonez, M. P. et al. Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1. Hum.Mol. Genet. 21, 2651-2662 (2012).
176. Maetzel, D. et al. Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick type C patient-specific iPS cells. Stem Cell Rep. 2, 866-880 (2014).
177. Sarkar, S. et al. Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease. Cell Rep. 5, 1 302-1315 (2013).
178. Meske, V., Erz, J., Priesnitz, T. & Ohm, T. G. The autophagic defect in Niemann-Pick disease type C neurons differs from somatic cells and reduces neuronal viability. Neurobiol. Dis. 64, 88-97 (2014).
179. Motori, E. et al. Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell. Metab. 18, 844-859 (2013).
180. Smith C. M.,Mayer J. A.,Duncan I. D. Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant J. Neurosci. 33, 8088-8100, 2013
181. Rangaraju, S. et al. Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice. J. Neurosci. 30, 11388-11397 (2010).
182. Di Malta , C., Fryer, J. D., Settembre, C. & Ballabio, A. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. Proc. Natl Acad. Sci. USA 109, E2334-E2342 (2012).
183. Deretic, V., Jiang, S. & Dupont, N. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol. 22, 397-406 (2012).
184. Kaufman, S. K. & Diamond, M. I. Prion-like propagation of protein aggregation and related therapeutic strategies. Neurotherapeutics 10, 371-382 (2013).
185. Danzer, K. M. et al. Exos omal cell-to-cell transmission of alpha synuclein oligomers. Mol. Neurodegener. 7, 42 (2012).
186. Ejlerskov, P. et al. Tubulin polymerization-promoting protein (TPPP/p25?) promotes unconventional secretion of ?-synuclein through exophagy by impairing autophagosome-lysosome fusion. J. Biol. Chem. 288, 17313-17335 (2013).
187. Lee, H. J. et al. Autophagic failure promotes the exocytosis and intercellular t ransfer of ?-synuclein. Exp. Mol. Med. 45, e22 (2013).
188. Nilsson, P. et al. A? secretion and plaque formation depend on autophagy. Cell Rep. 5, 61-69 (2013).
189. Nixon, R. A. Alzheimer neurodegeneration, autophagy, and Abeta secretion: the ins and outs (comment on DOI 10.1002/bies.201400002). Bioessays 36, 547 (2014).