The role of autophagy in neurodegenerative disease

Nature Medicine

Volumn 19, Issue 8, 2013, Pages 983-997

  Nixon, Ralph A ^a,b  

^a NATHAN S KLINE INSTITUTE FOR PSYCHIATRIC RESEARCH   (United States)

^b NEW YORK UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ESCRT PROTEIN; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 2; MEMBRANE PROTEIN; TAR DNA BINDING PROTEIN;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; AUTOLYSOSOME; AUTOPHAGOSOME; AUTOPHAGY; CELLULAR STRESS SIGNAL; CHAPERONE-MEDIATED AUTOPHAGY; DEGENERATIVE DISEASE; ENDOCYTOSIS; ENDOSOME; FRONTOTEMPORAL DEMENTIA; GAUCHER DISEASE; GENE MUTATION; GM1 GANGLIOSIDOSIS; HEREDITARY MOTOR SENSORY NEUROPATHY; HUMAN; HUNTINGTON CHOREA; HYPOXIC ISCHEMIC ENCEPHALOPATHY; INCLUSION BODY MYOSITIS; KENNEDY DISEASE; LOSS OF FUNCTION MUTATION; LYSOSOME; LYSOSOME MEMBRANE; LYSOSOME STORAGE DISEASE; MACROAUTOPHAGY; MEMBRANE COMPONENT; MICROTUBULE ORGANIZING CENTER; MOTOR NEURON DISEASE; MUCOPOLYSACCHARIDOSIS; MULTIPLE SULFATASE DEFICIENCY; MULTIVESICULAR BODY; NERVE CELL; NEURONAL CEROID LIPOFUSCINOSIS; NIEMANN PICK DISEASE; NONHUMAN; PAGET BONE DISEASE; PARKINSON DISEASE; PATHOGENESIS; PERRY SYNDROME; PRIORITY JOURNAL; PROTEIN MODIFICATION; PROTEIN PHOSPHORYLATION; REVIEW; SELECTIVE AUTOPHAGY; SIGNAL TRANSDUCTION;

AUTOPHAGY; HUMANS; LYSOSOMES; MODELS, BIOLOGICAL; NEURODEGENERATIVE DISEASES; PHAGOSOMES;

EID: 84882254367     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3232     Document Type: Review

References (231)

1. De Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435-492 (1966).
2. Boland, B. et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J. Neurosci. 28, 6926-6937 (2008).
3. Lee, S., Sato, Y. & Nixon, R.A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J. Neurosci. 31, 7817-7830 (2011).
4. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884 (2006).
5. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889 (2006).
6. Mizushima, N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22, 132-139 (2010).
7. Chan, E.Y., Longatti, A., McKnight, N.C. & Tooze, S.A. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol. Cell Biol. 29, 157-171 (2009).
8. Shang, L. & Wang, X. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy 7, 924-926 (2011).
9. Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280-293 (2010).
10. Stoica, L. et al. Selective pharmacogenetic inhibition of mammalian target of rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. Proc. Natl. Acad. Sci. USA 108, 3791-3796 (2011).
11. Jossin, Y. & Goffinet, A.M. Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. Mol. Cell Biol. 27, 7113-7124 (2007).
12. Narayanan, S.P., Flores, A.I., Wang, F. & Macklin, W.B. Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J. Neurosci. 29, 6860-6870 (2009).
13. Di Bartolomeo, S. et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J. Cell Biol. 191, 155-168 (2010).
14. Fimia, G.M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121-1125 (2007).
15. Suzuki, K., Kubota, Y., Sekito, T. & Ohsumi, Y. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12, 209-218 (2007).
16. Rubinsztein, D.C., Shpilka, T. & Elazar, Z. Mechanisms of autophagosome biogenesis. Curr. Biol. 22, R29-R34 (2012).
17. Ohsumi, Y. & Mizushima, N. Two ubiquitin-like conjugation systems essential for autophagy. Semin. Cell Dev. Biol. 15, 231-236 (2004).
18. Moreau, K., Ravikumar, B., Renna, M., Puri, C. & Rubinsztein, D.C. Autophagosome precursor maturation requires homotypic fusion. Cell 146, 303-317 (2011).
19. Reggiori, F. Autophagy: new questions from recent answers. ISRN Mol. Biol. 2012, 738718 (2012).
20. Subramani, S. & Malhotra, V. Non-autophagic roles of autophagy-related proteins. EMBO Rep. 14, 143-151 (2013).
21. Winslow, A.R. et al. α-synuclein impairs macroautophagy: implications for Parkinson's disease. J. Cell Biol. 190, 1023-1037 (2010).
22. Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13, 567-576 (2010).
23. Shibata, M. et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474-14485 (2006).
24. Aguado, C. et al. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum. Mol. Genet. 19, 2867-2876 (2010).
25. Filimonenko, M. et al. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol. Cell 38, 265-279 (2010).
26. Shaid, S., Brandts, C.H., Serve, H. & Dikic, I. Ubiquitination and selective autophagy. Cell Death Differ. 20, 21-30 (2013).
27. Deretic, V. Autophagy in infection. Curr. Opin. Cell Biol. 22, 252-262 (2010).
28. Johnson, C.W., Melia, T.J. & Yamamoto, A. Modulating macroautophagy: a neuronal perspective. Future Med. Chem. 4, 1715-1731 (2012).
29. Narendra, D.P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).
30. Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119-131 (2010).
31. Lee, J.Y., Nagano, Y., Taylor, J.P., Lim, K.L. & Yao, T.P. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J. Cell Biol. 189, 671-679 (2010).
32. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440-1446 (2011).
33. Chamoux, E., McManus, S., Laberge, G., Bisson, M. & Roux, S. Involvement of kinase PKC-ζ in the p62/p62(P392L)-driven activation of NF-κB in human osteoclasts. Biochim. Biophys. Acta 1832, 475-484 (2013).
34. Matsumoto, G., Wada, K., Okuno, M., Kurosawa, M. & Nukina, N. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol. Cell 44, 279-289 (2011).
35. Weishaupt, J.H. et al. A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany. Neurobiol. Aging 34, 1516.e9-15 (2013).
36. Ito, H. et al. Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation. Acta Neuropathol. 122, 223-229 (2011).
37. Korac, J. et al. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J. Cell Sci. 126, 580-592 (2013).
38. Ritz, D. et al. Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. Nat. Cell Biol. 13, 1116-1123 (2011).
39. Tresse, E. et al. VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6, 217-227 (2010).
40. Ju, J.S. et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J. Cell Biol. 187, 875-888 (2009).
41. Corti, O., Lesage, S. & Brice, A. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol. Rev. 91, 1161-1218 (2011).
42. Kim, N.C. et al. vcp is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78, 65-80 (2013).
43. Kaushik, S. & Cuervo, A.M. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407-417 (2012).
44. Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153-4170 (2009).
45. Orenstein, S.J. et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16, 394-406 (2013).
46. Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295 (2004).
47. Zhang, C. & Cuervo, A.M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, 959-965 (2008).
48. Yang, Q. et al. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323, 124-127 (2009).
49. Alvarez-Erviti, L. et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch. Neurol. 67, 1464-1472 (2010).
50. Korolchuk, V.I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453-460 (2011).
51. Kimura, S., Noda, T. & Yoshimori, T. Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct. Funct. 33, 109-122 (2008).
52. Larsen, K.E. & Sulzer, D. Autophagy in neurons: a review. Histol. Histopathol. 17, 897-908 (2002).
53. Hollenbeck, P.J. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J. Cell Biol. 121, 305-315 (1993).
54. Lee, J.A. & Gao, F.B. Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J. Neurosci. 29, 8506-8511 (2009).
55. Rusten, T.E. & Stenmark, H. How do ESCRT proteins control autophagy? J. Cell Sci. 122, 2179-2183 (2009).
56. Gutierrez, M.G., Munafo, D.B., Beron, W. & Colombo, M.I. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J. Cell Sci. 117, 2687-2697 (2004).
57. Renna, M. et al. Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. J. Cell Sci. 124, 469-482 (2011).
58. Koga, H., Kaushik, S. & Cuervo, A.M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052-3065 (2010).
59. Pankiv, S. et al. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J. Cell Biol. 188, 253-269 (2010).
60. Dodson, M.W., Zhang, T., Jiang, C., Chen, S. & Guo, M. Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum. Mol. Genet. 21, 1350-1363 (2012).
61. Uusi-Rauva, K. et al. Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments. Cell Mol. Life Sci. 69, 2075-2089 (2012).
62. Nixon, R.A. Niemann-Pick type C disease and Alzheimer's disease: the APP-endosome connection fattens up. Am. J. Pathol. 164, 757-761 (2004).
63. Ferrucci, M. et al. Protein clearing pathways in ALS. Arch. Ital. Biol. 149, 121-149 (2011).
64. Sasaki, S. Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 70, 349-359 (2011).
65. Ravikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37, 771-776 (2005).
66. Filimonenko, M. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179, 485-500 (2007).
67. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806-808 (2005).
68. Ganley, I.G., Wong, P.M., Gammoh, N. & Jiang, X. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol. Cell 42, 731-743 (2011).
69. McCray, B.A., Skordalakes, E. & Taylor, J.P. Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation. Hum. Mol. Genet. 19, 1033-1047 (2010).
70. Spinosa, M.R. et al. Functional characterization of Rab7 mutant proteins associated with Charcot-Marie-Tooth type 2B disease. J. Neurosci. 28, 1640-1648 (2008).
71. Tabata, K. et al. Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Mol. Biol. Cell 21, 4162-4172 (2010).
72. 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 their cellular function and leads to disturbed amphisome formation. FEBS Lett. 585, 730-736 (2011).
73. Hadano, S. et al. Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking. PLoS ONE 5, e9805 (2010).
74. Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623-635 (2009).
75. Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nat. Rev. Cancer 5, 886-897 (2005).
76. Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942-946 (2010).
77. Peña-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30, 3242-3258 (2011).
78. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T.P. & Guan, K.L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935-945 (2008).
79. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496-1501 (2008).
80. Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290-303 (2010).
81. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521-534 (2009).
82. Boland, B. & Nixon, R.A. Neuronal macroautophagy: from development to degeneration. Mol. Aspects Med. 27, 503-519 (2006).
83. Marshansky, V. The V-ATPase a2-subunit as a putative endosomal pH-sensor. Biochem. Soc. Trans. 35, 1092-1099 (2007).
84. Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson's disease. J. Neurosci. 30, 12535-12544 (2010).
85. Kirkegaard, T. et al. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463, 549-553 (2010).
86. Vitner, E.B., Platt, F.M. & Futerman, A.H. Common and uncommon pathogenic cascades in lysosomal storage diseases. J. Biol. Chem. 285, 20423-20427 (2010).
87. Siintola, E. et al. Cathepsin D deficiency underlies congential human neuronal ceriod-lipofuscinosis. Brain 129, 1438-1445 (2006).
88. Koike, M. et al. Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am. J. Pathol. 167, 1713-1728 (2005).
89. Elrick, M.J., Yu, T., Chung, C. & Lieberman, A.P. Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease. Hum. Mol. Genet. 21, 4876-4887 (2012).
90. Jin, L.W., Shie, F.S., Maezawa, I., Vincent, I. & Bird, T. Intracellular accumulation of amyloidogenic fragments of amyloid-β precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am. J. Pathol. 164, 975-985 (2004).
91. Soyombo, A.A. et al. TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J. Biol. Chem. 281, 7294-7301 (2006).
92. Curcio-Morelli, C. et al. Macroautophagy is defective in mucolipin-1-deficient mouse neurons. Neurobiol. Dis. 40, 370-377 (2010).
93. Steward, C.G. Neurological aspects of osteopetrosis. Neuropathol. Appl. Neurobiol. 29, 87-97 (2003).
94. Wartosch, L. & Stauber, T. A role for chloride transport in lysosomal protein degradation. Autophagy 6, 158-159 (2010).
95. Cao, Y. et al. Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J. Biol. Chem. 281, 20483-20493 (2006).
96. Boland, B. et al. Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J. Biol. Chem. 285, 37415-37426 (2010).
97. Nixon, R.A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113-122 (2005).
98. Nixon, R.A. & Yang, D.S. Autophagy failure in Alzheimer's disease-locating the primary defect. Neurobiol. Dis. 43, 38-45 (2011).
99. 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).
100. Cataldo, A.M. et al. Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J. Neuropathol. Exp. Neurol. 63, 821-830 (2004).
101. Ji, Z.S. et al. Reactivity of apolipoprotein E4 and amyloid β peptide: lysosomal stability and neurodegeneration. J. Biol. Chem. 281, 2683-2692 (2006).
102. Glabe, C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. J. Mol. Neurosci. 17, 137-145 (2001).
103. Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434-6451 (2008).
104. Nixon, R.A. & Yang, D. Autophagy and neuronal cell death in neurological disorders. Cold Spring Harb. Perspect. Biol. 4, a008839 (2012).
105. Cataldo, A.M. et al. Endocytic pathway abnormalities precede amyloid β deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am. J. Pathol. 157, 277-286 (2000).
106. Cataldo, A.M. et al. Down syndrome fibroblast model of Alzheimer-related endosome pathology. Accelerated endocytosis promotes late endocytic defects. Am. J. Pathol. 173, 370-384 (2008).
107. Singleton, A.B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).
108. Ebrahimi-Fakhari, D. et al. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein. J. Neurosci. 31, 14508-14520 (2011).
109. Yu, W.H. et al. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric α-synuclein. Am. J. Pathol. 175, 736-747 (2009).
110. Spencer, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29, 13578-13588 (2009).
111. Stefanis, L., Larsen, K.E., Rideout, H.J., Sulzer, D. & Greene, L.A. Expression of A53T mutant but not wild-type α-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J. Neurosci. 21, 9549-9560 (2001).
112. Dehay, B. et al. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl. Acad. Sci. USA 109, 9611-9616 (2012).
113. Rudenko, I.N., Chia, R. & Cookson, M.R. Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease? BMC Med. 10, 20 (2012).
114. Deng, X., Choi, H.G., Buhrlage, S.J. & Gray, N.S. Leucine-rich repeat kinase 2 inhibitors: a patent review (2006-2011). Expert Opin. Ther. Pat. 22, 1415-1426 (2012).
115. Manzoni, C. LRRK2 and autophagy: a common pathway for disease. Biochem. Soc. Trans. 40, 1147-1151 (2012).
116. MacLeod, D.A. et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77, 425-439 (2013).
117. Gómez-Suaga, P. et al. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum. Mol. Genet. 21, 511-525 (2012).
118. Westbroek, W., Gustafson, A.M. & Sidransky, E. Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol. Med. 17, 485-493 (2011).
119. Sardi, S.P. et al. CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc. Natl. Acad. Sci. USA 108, 12101-12106 (2011).
120. Xilouri, M., Vogiatzi, T., Vekrellis, K., Park, D. & Stefanis, L. Abberant α-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE 4, e5515 (2009).
121. Li, L., Zhang, X. & Le, W. Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 4, 290-293 (2008).
122. Morimoto, N. et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res. 1167, 112-117 (2007).
123. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585-595 (2004).
124. Lafay-Chebassier, C. et al. mTOR/p70S6k signalling alteration by A exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. J. Neurochem. 94, 215-225 (2005).
125. Koike, M. et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am. J. Pathol. 172, 454-469 (2008).
126. Zhu, J.H. et al. Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am. J. Pathol. 170, 75-86 (2007).
127. Rubinsztein, D.C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709-730 (2012).
128. Ching, J.K. et al. mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum. Mol. Genet. 22, 1167-1179 (2013).
129. Sarkar, S. & Rubinsztein, D.C. Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS J. 275, 4263-4270 (2008).
130. Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979 (2010).
131. Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107-13120 (2010).
132. Cortes, C.J., Qin, K., Cook, J., Solanki, A. & Mastrianni, J.A. Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Straussler-Scheinker disease. J. Neurosci. 32, 12396-12405 (2012).
133. Menzies, F.M. et al. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133, 93-104 (2010).
134. Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. & Rubinsztein, D.C. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009-25013 (2003).
135. Laplante, M. & Sabatini, D.M. mTOR signaling at a glance. J. Cell Sci. 122, 3589-3594 (2009).
136. Zhang, X. et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412-425 (2011).
137. Domanskyi, A. et al. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. FASEB J. 25, 2898-2910 (2011).
138. Thoreen, C.C. & Sabatini, D.M. Rapamycin inhibits mTORC1, but not completely. Autophagy 5, 725-726 (2009).
139. Williams, A. et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol. 4, 295-305 (2008).
140. Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. & Hiltunen, M. AMP-activated protein kinase: a potential player in Alzheimer's disease. J. Neurochem. 118, 460-474 (2011).
141. Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101-1111 (2005).
142. Fornai, F. et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 105, 2052-2057 (2008).
143. Feng, H.L. et al. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155, 567-572 (2008).
144. Pizzasegola, C. et al. Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph. Lateral Scler. 10, 221-228 (2009).
145. Forlenza, O.V., de Paula, V.J., Machado-Vieira, R., Diniz, B.S. & Gattaz, W.F. Does lithium prevent Alzheimer's disease? Drugs Aging 29, 335-342 (2012).
146. Sarkar, S., Davies, J.E., Huang, Z., Tunnacliffe, A. & Rubinsztein, D.C. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. J. Biol. Chem. 282, 5641-5652 (2007).
147. Rubinsztein, D.C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682-695 (2011).
148. Maher, P. et al. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS ONE 6, e21226 (2011).
149. Magnaudeix, A. et al. PP2A blockade inhibits autophagy and causes intraneuronal accumulation of ubiquitinated proteins. Neurobiol. Aging 34, 770-790 (2013).
150. Nascimento-Ferreira, I. et al. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease. Brain 134, 1400-1415 (2011).
151. Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201-206 (2013).
152. Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228-233 (2011).
153. Jeong, H. et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137, 60-72 (2009).
154. Qi, L. et al. The role of chaperone-mediated autophagy in huntingtin degradation. PLoS ONE 7, e46834 (2012).
155. Chatellier, J., Hill, F., Lund, P.A. & Fersht, A.R. In vivo activities of GroEL minichaperones. Proc. Natl. Acad. Sci. USA 95, 9861-9866 (1998).
156. 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).
157. Sun, B. et al. Cystatin C-cathepsin B axis regulates amyloid β levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron 60, 247-257 (2008).
158. Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703-714 (2006).
159. Butler, D. et al. Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models. PLoS ONE 6, e20501 (2011).
160. Conn, P.M. & Ulloa-Aguirre, A. Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv. Pharmacol. 62, 109-141 (2011).
161. Schultz, M.L., Tecedor, L., Chang, M. & Davidson, B.L. Clarifying lysosomal storage diseases. Trends Neurosci. 34, 401-410 (2011).
162. Tamboli, I.Y. et al. Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Aβ generation. J. Neurosci. 31, 1837-1849 (2011).
163. Keilani, S. et al. Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide. J. Neurosci. 32, 5223-5236 (2012).
164. Davidson, C.D. et al. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS ONE 4, e6951 (2009).
165. Sulzer, D. et al. Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease. J. Neurochem. 106, 24-36 (2008).
166. Zhang, L. et al. Calcium overload is associated with lipofuscin formation in human retinal pigment epithelial cells fed with photoreceptor outer segments. Eye (Lond.) 25, 519-527 (2011).
167. Pék, G., Fulop, T. & Zs-Nagy, I. Gerontopsychological studies using NAI ('Nurnberger Alters-Inventar') on patients with organic psychosyndrome (DSM III, Category 1) treated with centrophenoxine in a double blind, comparative, randomized clinical trial. Arch. Gerontol. Geriatr. 9, 17-30 (1989).
168. Parenti, G., Pignata, C., Vajro, P. & Salerno, M. New strategies for the treatment of lysosomal storage diseases. Int. J. Mol. Med. 31, 11-20 (2013).
169. Medina, D.L. et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21, 421-430 (2011).
170. Yuyama, K., Sun, H., Mitsutake, S. & Igarashi, Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J. Biol. Chem. 287, 10977-10989 (2012).
171. Yogalingam, G. et al. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev. Cell 15, 74-86 (2008).
172. LaPlante, J.M. et al. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol. Genet. Metab. 89, 339-348 (2006).
173. Rajendran, L. et al. Alzheimer's disease β-amyloid peptides are released in association with exosomes. Proc. Natl. Acad. Sci. USA 103, 11172-11177 (2006).
174. Polymenidou, M. & Cleveland, D.W. Prion-like spread of protein aggregates in neurodegeneration. J. Exp. Med. 209, 889-893 (2012).
175. Yamashima, T. Hsp70.1 and related lysosomal factors for necrotic neuronal death. J. Neurochem. 120, 477-494 (2012).
176. Trinchese, F. et al. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J. Clin. Invest. 118, 2796-2807 (2008).
177. Johansson, A.C. et al. Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis 15, 527-540 (2010).
178. Avrahami, L. et al. Inhibition of GSK-3 ameliorates β-amyloid(A- β) pathology and restores lysosomal acidification and mTOR activity in the Alzheimer's disease mouse model: in vivo and in vitro studies. J. Biol. Chem. 288, 1295-1306 (2013).
179. Guha, S. et al. Stimulation of the D5 dopamine receptor acidifies the lysosomal pH of retinal pigmented epithelial cells and decreases accumulation of autofluorescent photoreceptor debris. J. Neurochem. 122, 823-833 (2012).
180. Behrends, C., Sowa, M.E., Gygi, S.P. & Harper, J.W. Network organization of the human autophagy system. Nature 466, 68-76 (2010).
181. Panza, F. et al. Current epidemiological approaches to the metabolic-cognitive syndrome. J. Alzheimers Dis. 30 (suppl. 2), S31-S75 (2012).
182. Singh, R. & Cuervo, A.M. Lipophagy: connecting autophagy and lipid metabolism. Int. J. Cell Biol. 2012, 282041 (2012).
183. Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488-492 (2000).
184. Fujita, N. et al. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol. Biol. Cell 19, 4651-4659 (2008).
185. Durcan, T.M., Kontogiannea, M., Bedard, N., Wing, S.S. & Fon, E.A. Ataxin-3 deubiquitination is coupled to Parkin ubiquitination via E2 ubiquitin-conjugating enzyme. J. Biol. Chem. 287, 531-541 (2012).
186. Pasquali, L. et al. The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis. CNS Neurol. Disord. Drug Targets 9, 268-278 (2010).
187. Laird, F.M. et al. Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking. J. Neurosci. 28, 1997-2005 (2008).
188. Farrer, M.J. et al. DCTN1 mutations in Perry syndrome. Nat. Genet. 41, 163-165 (2009).
189. Harms, M.B. et al. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78, 1714-1720 (2012).
190. Wolfe, D.M. et al. Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 37, 1949-1961 (2013).
191. Bhargava, A. et al. Osteopetrosis mutation R444L causes endoplasmic reticulum retention and misprocessing of vacuolar H+-ATPase a3 subunit. J. Biol. Chem. 287, 26829-26839 (2012).
192. Rajan, I., Read, R., Small, D.L., Perrard, J. & Vogel, P. An alternative splicing variant in Clcn7?/? mice prevents osteopetrosis but not neural and retinal degeneration. Vet. Pathol. 48, 663-675 (2011).
193. Settembre, C. et al. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17, 119-129 (2008).
194. Cheng, H.C. et al. Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J. Neurosci. 31, 2125-2135 (2011).
195. Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433-442 (2006).
196. Wang, I.F. et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc. Natl. Acad. Sci. USA 109, 15024-15029 (2012).
197. Jiang, T.F. et al. Curcumin ameliorates the neurodegenerative pathology in A53T α-synuclein cell model of Parkinson's disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. J. Neuroimmune Pharmacol. 8, 356-369 (2013).
198. Wu, Y. et al. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease. Neurosignals 19, 163-174 (2011).
199. Steele, J.W. et al. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol. Psychiatry advance online publication, http://dx.doi.org/10.1038/mp.2012.115 (7 August 2012).
200. Bezprozvanny, I. The rise and fall of Dimebon. Drug News Perspect. 23, 518-523 (2010).
201. Lan, D.M. et al. Effect of trehalose on PC12 cells overexpressing wild-type or A53T mutant α-synuclein. Neurochem. Res. 37, 2025-2032 (2012).
202. Rodríguez-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).
203. Schaeffer, V. et al. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135, 2169-2177 (2012).
204. 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).
205. Vingtdeux, V. et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J. Biol. Chem. 285, 9100-9113 (2010).
206. Giri, S., Khan, M., Nath, N., Singh, I. & Singh, A.K. The role of AMPK in psychosine mediated effects on oligodendrocytes and astrocytes: implication for Krabbe disease. J. Neurochem. 105, 1820-1833 (2008).
207. Corcoran, N.M. et al. Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J. Clin. Neurosci. 17, 1025-1033 (2010).
208. Chiruta, C., Schubert, D., Dargusch, R. & Maher, P. Chemical modification of the multitarget neuroprotective compound fisetin. J. Med. Chem. 55, 378-389 (2012).
209. Kickstein, E. et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl. Acad. Sci. USA 107, 21830-21835 (2010).
210. Ma, T.C. et al. Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci. Lett. 411, 98-103 (2007).
211. Jaeger, P.A. et al. Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS ONE 5, e11102 (2010).
212. Shoghi-Jadid, K. et al. Localization of neurofibrillary tangles and β-amyloid plaques in the brains of living patients with Alzheimer disease 2455. Am. J. Geriatr. Psychiatry 10, 24-35 (2002).
213. Echaniz-Laguna, A., Bousiges, O., Loeffler, J.P. & Boutillier, A.L. Histone deacetylase inhibitors: therapeutic agents and research tools for deciphering motor neuron diseases. Curr. Med. Chem. 15, 1263-1273 (2008).
214. Kilgore, M. et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 35, 870-880 (2010).
215. Yoshiike, Y. et al. Adaptive responses to alloxan-induced mild oxidative stress ameliorate certain tauopathy phenotypes. Aging Cell 11, 51-62 (2012).
216. Du, G. et al. Drosophila histone deacetylase 6 protects dopaminergic neurons against α-synuclein toxicity by promoting inclusion formation. Mol. Biol. Cell 21, 2128-2137 (2010).
217. Jia, H., Kast, R.J., Steffan, J.S. & Thomas, E.A. Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Hum. Mol. Genet. 21, 5280-5293 (2012).
218. Pemberton, S. et al. Hsc70 protein interaction with soluble and fibrillar α-synuclein. J. Biol. Chem. 286, 34690-34699 (2011).
219. Qiao, L. et al. Lysosomal enzyme cathepsin D protects against α-synuclein aggregation and toxicity. Mol. Brain 1, 17 (2008).
220. Valenzano, K.J. et al. Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. Assay Drug Dev. Technol. 9, 213-235 (2011).
221. Decressac, M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl. Acad. Sci. USA 110, E1817-E1826 (2013).
222. Tsunemi, T. et al. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra97 (2012).
223. Yao, J. et al. Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J. Exp. Med. 209, 2501-2513 (2012).
224. Matsuo, M. et al. Effects of cyclodextrin in two patients with Niemann-Pick type C disease. Mol. Genet. Metab. 108, 76-81 (2013).
225. Platt, F.M. & Jeyakumar, M. Substrate reduction therapy. Acta Paediatr. Suppl. 97, 88-93 (2008).
226. Appelqvist, H. et al. Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content. PLoS ONE 7, e50262 (2012).
227. Nehru, B., Verma, R., Khanna, P. & Sharma, S.K. Behavioral alterations in rotenone model of Parkinson's disease: attenuation by co-treatment of centrophenoxine. Brain Res. 1201, 122-127 (2008).
228. Parr, C. et al. Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-β precursor protein. Mol. Cell Biol. 32, 4410-4418 (2012).
229. Giampà, C. et al. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease. PLoS ONE 5, e13417 (2010).
230. Spampanato, C. et al. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol. Med. 5, 691-706 (2013).
231. Chen, F.W., Li, C. & Ioannou, Y.A. Cyclodextrin induces calcium-dependent lysosomal exocytosis. PLoS ONE 5, e15054 (2010).