Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The role of autophagy in neurodegenerative disease

Abstract

Autophagy is a lysosomal degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and protein aggregates. These substrates reach lysosomes by several distinct mechanisms, including delivery within endosomes as well as autophagosomes. Completion of digestion involves dynamic interactions among compartments of the autophagic and endocytic pathways. Neurons are particularly vulnerable to disruptions of these interactions, especially as the brain ages. Not surprisingly, mutations of genes regulating autophagy cause neurodegenerative diseases across the age spectrum with exceptional frequency. In late-onset disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and familial Parkinson's disease, defects arise at different stages of the autophagy pathway and have different implications for pathogenesis and therapy. This Review provides an overview of the role of autophagy in neurodegenerative disease, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: An overview of macroautophagy.
Figure 2: Autophagy induction and autophagosome biogenesis.
Figure 3: Substrate recognition and selective autophagy.
Figure 4: Clearance of autophagic substrates.

References

  1. De Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435–492 (1966).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    CAS  PubMed  Google Scholar 

  5. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  6. Mizushima, N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22, 132–139 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  8. Shang, L. & Wang, X. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy 7, 924–926 (2011).

    PubMed  Google Scholar 

  9. Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fimia, G.M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121–1125 (2007).

    CAS  PubMed  Google Scholar 

  15. Suzuki, K., Kubota, Y., Sekito, T. & Ohsumi, Y. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12, 209–218 (2007).

    CAS  PubMed  Google Scholar 

  16. Rubinsztein, D.C., Shpilka, T. & Elazar, Z. Mechanisms of autophagosome biogenesis. Curr. Biol. 22, R29–R34 (2012).

    CAS  PubMed  Google Scholar 

  17. Ohsumi, Y. & Mizushima, N. Two ubiquitin-like conjugation systems essential for autophagy. Semin. Cell Dev. Biol. 15, 231–236 (2004).

    CAS  PubMed  Google Scholar 

  18. Moreau, K., Ravikumar, B., Renna, M., Puri, C. & Rubinsztein, D.C. Autophagosome precursor maturation requires homotypic fusion. Cell 146, 303–317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Reggiori, F. Autophagy: new questions from recent answers. ISRN Mol. Biol. 2012, 738718 (2012).

    PubMed  PubMed Central  Google Scholar 

  20. Subramani, S. & Malhotra, V. Non-autophagic roles of autophagy-related proteins. EMBO Rep. 14, 143–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Winslow, A.R. et al. α-synuclein impairs macroautophagy: implications for Parkinson's disease. J. Cell Biol. 190, 1023–1037 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13, 567–576 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Shibata, M. et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474–14485 (2006).

    CAS  PubMed  Google Scholar 

  24. Aguado, C. et al. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum. Mol. Genet. 19, 2867–2876 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Filimonenko, M. et al. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol. Cell 38, 265–279 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Shaid, S., Brandts, C.H., Serve, H. & Dikic, I. Ubiquitination and selective autophagy. Cell Death Differ. 20, 21–30 (2013).

    CAS  PubMed  Google Scholar 

  27. Deretic, V. Autophagy in infection. Curr. Opin. Cell Biol. 22, 252–262 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Johnson, C.W., Melia, T.J. & Yamamoto, A. Modulating macroautophagy: a neuronal perspective. Future Med. Chem. 4, 1715–1731 (2012).

    CAS  PubMed  Google Scholar 

  29. Narendra, D.P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).

    PubMed  PubMed Central  Google Scholar 

  30. Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  36. Ito, H. et al. Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation. Acta Neuropathol. 122, 223–229 (2011).

    PubMed  Google Scholar 

  37. Korac, J. et al. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J. Cell Sci. 126, 580–592 (2013).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaushik, S. & Cuervo, A.M. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407–417 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153–4170 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Orenstein, S.J. et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16, 394–406 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang, Q. et al. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323, 124–127 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Alvarez-Erviti, L. et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch. Neurol. 67, 1464–1472 (2010).

    PubMed  Google Scholar 

  50. Korolchuk, V.I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453–460 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kimura, S., Noda, T. & Yoshimori, T. Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct. Funct. 33, 109–122 (2008).

    CAS  PubMed  Google Scholar 

  52. Larsen, K.E. & Sulzer, D. Autophagy in neurons: a review. Histol. Histopathol. 17, 897–908 (2002).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Rusten, T.E. & Stenmark, H. How do ESCRT proteins control autophagy? J. Cell Sci. 122, 2179–2183 (2009).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  57. Renna, M. et al. Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. J. Cell Sci. 124, 469–482 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Koga, H., Kaushik, S. & Cuervo, A.M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052–3065 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  63. Ferrucci, M. et al. Protein clearing pathways in ALS. Arch. Ital. Biol. 149, 121–149 (2011).

    PubMed  Google Scholar 

  64. Sasaki, S. Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 70, 349–359 (2011).

    PubMed  Google Scholar 

  65. Ravikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37, 771–776 (2005).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  74. Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623–635 (2009).

    CAS  PubMed  Google Scholar 

  75. Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nat. Rev. Cancer 5, 886–897 (2005).

    CAS  PubMed  Google Scholar 

  76. Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Peña-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30, 3242–3258 (2011).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Boland, B. & Nixon, R.A. Neuronal macroautophagy: from development to degeneration. Mol. Aspects Med. 27, 503–519 (2006).

    CAS  PubMed  Google Scholar 

  83. Marshansky, V. The V-ATPase a2-subunit as a putative endosomal pH-sensor. Biochem. Soc. Trans. 35, 1092–1099 (2007).

    CAS  PubMed  Google Scholar 

  84. Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson's disease. J. Neurosci. 30, 12535–12544 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kirkegaard, T. et al. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease–associated lysosomal pathology. Nature 463, 549–553 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Siintola, E. et al. Cathepsin D deficiency underlies congential human neuronal ceriod-lipofuscinosis. Brain 129, 1438–1445 (2006).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Soyombo, A.A. et al. TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J. Biol. Chem. 281, 7294–7301 (2006).

    CAS  PubMed  Google Scholar 

  92. Curcio-Morelli, C. et al. Macroautophagy is defective in mucolipin-1–deficient mouse neurons. Neurobiol. Dis. 40, 370–377 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Steward, C.G. Neurological aspects of osteopetrosis. Neuropathol. Appl. Neurobiol. 29, 87–97 (2003).

    CAS  PubMed  Google Scholar 

  94. Wartosch, L. & Stauber, T. A role for chloride transport in lysosomal protein degradation. Autophagy 6, 158–159 (2010).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  96. Boland, B. et al. Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J. Biol. Chem. 285, 37415–37426 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  98. Nixon, R.A. & Yang, D.S. Autophagy failure in Alzheimer's disease—locating the primary defect. Neurobiol. Dis. 43, 38–45 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  102. Glabe, C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. J. Mol. Neurosci. 17, 137–145 (2001).

    CAS  PubMed  Google Scholar 

  103. Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008).

    CAS  PubMed  Google Scholar 

  104. Nixon, R.A. & Yang, D. Autophagy and neuronal cell death in neurological disorders. Cold Spring Harb. Perspect. Biol. 4, a008839 (2012).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Singleton, A.B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  115. Manzoni, C. LRRK2 and autophagy: a common pathway for disease. Biochem. Soc. Trans. 40, 1147–1151 (2012).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  118. Westbroek, W., Gustafson, A.M. & Sidransky, E. Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol. Med. 17, 485–493 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  121. Li, L., Zhang, X. & Le, W. Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 4, 290–293 (2008).

    CAS  PubMed  Google Scholar 

  122. Morimoto, N. et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res. 1167, 112–117 (2007).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  125. Koike, M. et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am. J. Pathol. 172, 454–469 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  129. Sarkar, S. & Rubinsztein, D.C. Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS J. 275, 4263–4270 (2008).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  135. Laplante, M. & Sabatini, D.M. mTOR signaling at a glance. J. Cell Sci. 122, 3589–3594 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  137. Domanskyi, A. et al. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. FASEB J. 25, 2898–2910 (2011).

    CAS  PubMed  Google Scholar 

  138. Thoreen, C.C. & Sabatini, D.M. Rapamycin inhibits mTORC1, but not completely. Autophagy 5, 725–726 (2009).

    CAS  PubMed  Google Scholar 

  139. Williams, A. et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol. 4, 295–305 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  141. Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101–1111 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Fornai, F. et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 105, 2052–2057 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  147. Rubinsztein, D.C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).

    CAS  PubMed  Google Scholar 

  148. Maher, P. et al. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS ONE 6, e21226 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Magnaudeix, A. et al. PP2A blockade inhibits autophagy and causes intraneuronal accumulation of ubiquitinated proteins. Neurobiol. Aging 34, 770–790 (2013).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  151. Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Jeong, H. et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137, 60–72 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Qi, L. et al. The role of chaperone-mediated autophagy in huntingtin degradation. PLoS ONE 7, e46834 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703–714 (2006).

    CAS  PubMed  Google Scholar 

  159. Butler, D. et al. Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models. PLoS ONE 6, e20501 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Conn, P.M. & Ulloa-Aguirre, A. Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv. Pharmacol. 62, 109–141 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Schultz, M.L., Tecedor, L., Chang, M. & Davidson, B.L. Clarifying lysosomal storage diseases. Trends Neurosci. 34, 401–410 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  169. Medina, D.L. et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21, 421–430 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Yogalingam, G. et al. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev. Cell 15, 74–86 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. LaPlante, J.M. et al. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol. Genet. Metab. 89, 339–348 (2006).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Polymenidou, M. & Cleveland, D.W. Prion-like spread of protein aggregates in neurodegeneration. J. Exp. Med. 209, 889–893 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Yamashima, T. Hsp70.1 and related lysosomal factors for necrotic neuronal death. J. Neurochem. 120, 477–494 (2012).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Johansson, A.C. et al. Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis 15, 527–540 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Behrends, C., Sowa, M.E., Gygi, S.P. & Harper, J.W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Panza, F. et al. Current epidemiological approaches to the metabolic-cognitive syndrome. J. Alzheimers Dis. 30 (suppl. 2), S31–S75 (2012).

    PubMed  Google Scholar 

  182. Singh, R. & Cuervo, A.M. Lipophagy: connecting autophagy and lipid metabolism. Int. J. Cell Biol. 2012, 282041 (2012).

    PubMed  PubMed Central  Google Scholar 

  183. Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488–492 (2000).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Farrer, M.J. et al. DCTN1 mutations in Perry syndrome. Nat. Genet. 41, 163–165 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Harms, M.B. et al. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78, 1714–1720 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  193. Settembre, C. et al. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17, 119–129 (2008).

    CAS  PubMed  Google Scholar 

  194. Cheng, H.C. et al. Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J. Neurosci. 31, 2125–2135 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  198. Wu, Y. et al. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease. Neurosignals 19, 163–174 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  203. Schaeffer, V. et al. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135, 2169–2177 (2012).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  208. Chiruta, C., Schubert, D., Dargusch, R. & Maher, P. Chemical modification of the multitarget neuroprotective compound fisetin. J. Med. Chem. 55, 378–389 (2012).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Ma, T.C. et al. Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci. Lett. 411, 98–103 (2007).

    CAS  PubMed  Google Scholar 

  211. Jaeger, P.A. et al. Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS ONE 5, e11102 (2010).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  215. Yoshiike, Y. et al. Adaptive responses to alloxan-induced mild oxidative stress ameliorate certain tauopathy phenotypes. Aging Cell 11, 51–62 (2012).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Pemberton, S. et al. Hsc70 protein interaction with soluble and fibrillar α-synuclein. J. Biol. Chem. 286, 34690–34699 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Qiao, L. et al. Lysosomal enzyme cathepsin D protects against α-synuclein aggregation and toxicity. Mol. Brain 1, 17 (2008).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  223. Yao, J. et al. Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J. Exp. Med. 209, 2501–2513 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Matsuo, M. et al. Effects of cyclodextrin in two patients with Niemann-Pick type C disease. Mol. Genet. Metab. 108, 76–81 (2013).

    CAS  PubMed  Google Scholar 

  225. Platt, F.M. & Jeyakumar, M. Substrate reduction therapy. Acta Paediatr. Suppl. 97, 88–93 (2008).

    Google Scholar 

  226. Appelqvist, H. et al. Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content. PLoS ONE 7, e50262 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  230. Spampanato, C. et al. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol. Med. 5, 691–706 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Chen, F.W., Li, C. & Ioannou, Y.A. Cyclodextrin induces calcium-dependent lysosomal exocytosis. PLoS ONE 5, e15054 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I gratefully acknowledge the expert assistance of N. Piorkowski in manuscript preparation and C. Peterhoff in figure preparation and thank past and present lab members for contributing to the described work and for helpful discussions. Studies from this laboratory are supported by the US National Institute on Aging (P01AG017617 and R01AG005604).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ralph A Nixon.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nixon, R. The role of autophagy in neurodegenerative disease. Nat Med 19, 983–997 (2013). https://doi.org/10.1038/nm.3232

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3232

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing