Autophagy is essential for neuronal homeostasis, and its dysfunction has been directly linked to a growing number of neurodegenerative disorders. The reasons behind autophagic failure in degenerating neurons can be very diverse because of the different steps required for autophagy and the characterization of the molecular players involved in each of them. Understanding the step(s) affected in the autophagic process in each disorder could explain differences in the course of these pathologies and will be essential to developing targeted therapeutic approaches for each disease based on modulation of autophagy. Here we present examples of different types of autophagic dysfunction described in common neurodegenerative disorders and discuss the prospect of exploring some of the recently identified autophagic variants and the interactions among autophagic and non-autophagic proteolytic systems as possible future therapeutic targets.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Location, location, location: subcellular protein partitioning in proteostasis and aging
Biophysical Reviews Open Access 19 November 2021
The neuroprotective effects of activated α7 nicotinic acetylcholine receptor against mutant copper–zinc superoxide dismutase 1-mediated toxicity
Scientific Reports Open Access 17 December 2020
Quantitative analysis of global protein stability rates in tissues
Scientific Reports Open Access 29 September 2020
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Mizushima, N., Levine, B., Cuervo, A.M. & Klionsky, D.J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
He, C. & Klionsky, D.J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93 (2009).
Klionsky, D.J. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931–937 (2007).
Rubinsztein, D.C., Gestwicki, J.E., Murphy, L.O. & Klionsky, D.J. Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 6, 304–312 (2007).
Winslow, A.R. & Rubinsztein, D.C. Autophagy in neurodegeneration and development. Biochim. Biophys. Acta 1782, 723–729 (2008).
Nixon, R.A., Yang, D.S. & Lee, J.H. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4, 590–599 (2008).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008).
Komatsu, M. et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. USA 104, 14489–14494 (2007).
Wang, Q.J. et al. Induction of autophagy in axonal dystrophy and degeneration. J. Neurosci. 26, 8057–8068 (2006).
Fimia, G.M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121–1125 (2007).
Kegel, K.B. et al. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J. Neurosci. 20, 7268–7278 (2000).
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).
Yang, Y., Fukui, K., Koike, T. & Zheng, X. Induction of autophagy in neurite degeneration of mouse superior cervical ganglion neurons. Eur. J. Neurosci. 26, 2979–2988 (2007).
Mortimore, G.E., Poso, A.R. & Lardeux, B.R. Mechanism and regulation of protein degradation in liver. Diabetes Metab. Rev. 5, 49–70 (1989).
Cuervo, A.M. Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol. Metab. 21, 142–150 (2010).
Dice, J.F. Chaperone-mediated autophagy. Autophagy 3, 295–299 (2007).
Meijer, A.J. & Codogno, P. Autophagy: regulation and role in disease. Crit. Rev. Clin. Lab. Sci. 46, 210–240 (2009).
Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
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).
Ravikumar, B., Duden, R. & Rubinsztein, D. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).
Stefanis, L., Larsen, K., Rideout, H., Sulzer, D. & Greene, L. Expression of A53T mutant but not wild-type alpha-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).
Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. & Rubinsztein, D.C. Alpha-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).
Morimoto, N. et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res. 1167, 112–117 (2007).
Li, L., Zhang, X. & Le, W. Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 4, 290–293 (2008).
Iwata, A. et al. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc. Natl. Acad. Sci. USA 102, 13135–13140 (2005).
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).
Samara, C., Syntichaki, P. & Tavernarakis, N. Autophagy is required for necrotic cell death in Caenorhabditis elegans. Cell Death Differ. 15, 105–112 (2008).
Uchiyama, Y., Koike, M., Shibata, M. & Sasaki, M. Autophagic neuron death. Methods Enzymol. 453, 33–51 (2009).
Cherra, S.J. & Chu, C.T. Autophagy in neuroprotection and neurodegeneration: a question of balance. Future Neurol. 3, 309–323 (2008).
Rubinsztein, D.C. et al. In search of an “autophagomometer”. Autophagy 5, 585–589 (2009).
Axe, E.L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).
Ohsumi, Y. & Mizushima, N. Two ubiquitin-like conjugation systems essential for autophagy. Semin. Cell Dev. Biol. 15, 231–236 (2004).
Simonsen, A. et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4, 176–184 (2008).
Kihara, A., Kabeya, Y., Ohsumi, Y. & Yoshimori, T. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep. 2, 330–335 (2001).
Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11, 468–476 (2009).
Erlich, S., Shohami, E. & Pinkas-Kramarski, R. Neurodegeneration induces upregulation of Beclin 1. Autophagy 2, 49–51 (2006).
Shibata, M. et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474–14485 (2006).
Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).
Pattingre, S. et al. Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J. Biol. Chem. 284, 2719–2728 (2009).
Kanazawa, T. et al. Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. J. Biol. Chem. 279, 8452–8459 (2004).
Rosenbluth, J.M. & Pietenpol, J.A. mTOR regulates autophagy-associated genes downstream of p73. Autophagy 5, 114–116 (2009).
Kraft, C., Reggiori, F. & Peter, M. Selective types of autophagy in yeast. Biochim. Biophys. Acta 1793, 1404–1412 (2009).
Kirkin, V., McEwan, D.G., Novak, I. & Dikic, I. A role for ubiquitin in selective autophagy. Mol. Cell 34, 259–269 (2009).
Sarkar, S., Ravikumar, B. & Rubinsztein, D.C. Autophagic clearance of aggregate-prone proteins associated with neurodegeneration. Methods Enzymol. 453, 83–110 (2009).
Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
Tan, J.M., Wong, E.S., Dawson, V.L., Dawson, T.M. & Lim, K.L. Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy 4, 251–253 (2007).
Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007).
Zheng, Y.T. et al. The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J. Immunol. 183, 5909–5916 (2009).
Kim, P.K., Hailey, D.W., Mullen, R.T. & Lippincott-Schwartz, J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc. Natl. Acad. Sci. USA 105, 20567–20574 (2008).
Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516 (2009).
Thurston, T.L.M., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10, 1215–1221 (2009).
Wong, E.S. et al. Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum. Mol. Genet. 17, 2570–2582 (2008).
Jeong, H. et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137, 60–72 (2009).
Mookerjee, S. et al. Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J. Neurosci. 29, 15134–15144 (2009).
Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13, 567–576 (2010).
Webb, J.L., Ravikumar, B. & Rubinsztein, D.C. Microtubule disruption inhibits autophagosome-lysosome fusion: implications for studying the roles of aggresomes in polyglutamine diseases. Int. J. Biochem. Cell Biol. 36, 2541–2550 (2004).
Iwata, A., Riley, B.E., Johnston, J.A. & Kopito, R.R. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J. Biol. Chem. 280, 40282–40292 (2005).
Kochl, R., Hu, X.W., Chan, E.Y. & Tooze, S.A. Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7, 129–145 (2006).
Kimura, S., Noda, T. & Yoshimori, T. Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct. Funct. 33, 109–122 (2008).
Pacheco, C.D., Elrick, M.J. & Lieberman, A.P. Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis. Hum. Mol. Genet. 18, 956–965 (2009).
Lee, H.Y. et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality control autophagy. EMBO J. 29, 969–980 (2010).
Settembre, C. et al. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17, 119–129 (2008).
Vergarajauregui, S., Connelly, P.S., Daniels, M.P. & Puertollano, R. Autophagic dysfunction in mucolipidosis type IV patients. Hum. Mol. Genet. 17, 2723–2737 (2008).
Bi, X. & Liao, G. Autophagic-lysosomal dysfunction and neurodegeneration in Niemann-Pick Type C mice: lipid starvation or indigestion? Autophagy 3, 646–648 (2007).
Lee, J.-H. et al. Presenilin 1 (PS1) is required for v-ATPase targeting and autolysosome acidification. Cell (in the press).
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).
Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).
Yu, W.H. et al. Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J. Cell Biol. 171, 87–98 (2005).
Kaasik, A., Rikk, T., Piirsoo, A., Zharkovsky, T. & Zharkovsky, A. Up-regulation of lysosomal cathepsin L and autophagy during neuronal death induced by reduced serum and potassium. Eur. J. Neurosci. 22, 1023–1031 (2005).
Massey, A.C., Kaushik, S., Sovak, G., Kiffin, R. & Cuervo, A.M. Consequences of the selective blockage of chaperone-mediated autophagy. Proc. Natl. Acad. Sci. USA 103, 5805–5810 (2006).
Kaushik, S., Massey, A., Mizushima, N. & Cuervo, A.M. Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol. Biol. Cell 19, 2179–2192 (2008).
Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T. & Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).
Martinez-Vicente, M. et al. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest. 118, 777–788 (2008).
Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153–4170 (2009).
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).
Urwin, H., Ghazi-Noori, S., Collinge, J. & Isaacs, A. The role of CHMP2B in frontotemporal dementia. Biochem. Soc. Trans. 37, 208–212 (2009).
Rusten, T.E. et al. ESCRTs and Fab1 regulate distinct steps of autophagy. Curr. Biol. 17, 1817–1825 (2007).
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).
Eskelinen, E.L. et al. Role of LAMP-2 in lysosome biogenesis and autophagy. Mol. Biol. Cell 13, 3355–3368 (2002).
Massey, A.C., Follenzi, A., Kiffin, R., Zhang, C. & Cuervo, A.M. Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy 4, 442–456 (2008).
Kovacs, G.G. & Herbert, B. Prion diseases: from protein to cell pathology. Am. J. Pathol. 172, 555–565 (2008).
Frost, B. & Diamond, M.I. Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 11, 155–159 (2009).
Heiseke, A., Aguib, Y. & Schatzl, H.M. Autophagy, prion infection and their mutual interactions. Curr. Issues Mol. Biol. 12, 87–98 (2009).
Nedelsky, N.B., Todd, P.K. & Taylor, J.P. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim. Biophys. Acta 1782, 691–699 (2008).
Pandey, U.B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).
Ding, Q. et al. Characterization of chronic low-level proteasome inhibition on neural homeostasis. J. Neurochem. 86, 489–497 (2003).
Pan, T. et al. Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16–25 (2008).
Kirkin, V., Lamark, T., Johansen, T. & Dikic, I. NBR1 cooperates with p62 in selective autophagy of ubiquitinated targets. Autophagy 5, 732–733 (2009).
Zhang, X.D. et al. p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum. Autophagy 5, 339–350 (2009).
Korolchuk, V.I., Mansilla, A., Menzies, F.M. & Rubinsztein, D.C. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517–527 (2009).
Ichimura, Y., Kominami, E., Tanaka, K. & Komatsu, M. Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy 4, 1063–1066 (2008).
Dagda, R.K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843–13855 (2009).
Chu, C.T., Zhu, J. & Dagda, R. Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress: implications for neurodegeneration and cell death. Autophagy 3, 663–666 (2007).
Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).
Sarkar, S. et al. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).
Yamamoto, A., Cremona, M. & Rothman, J. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719–731 (2006).
Scarlatti, F., Maffei, R., Beau, I., Codogno, P. & Ghidoni, R. Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ. 15, 1318–1329 (2008).
Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009).
We thank the numerous colleagues in the field of autophagy who through their animated discussions have helped shape this review and S. Kaushik and S. Orenstein for critically reading the manuscript. Work in our laboratory is supported by US National Institutes of Health grants from the National Institute on Aging (AG021904, AG031782), the National Institute of Diabetes and Digestive and Kidney Diseases (DK041918), the National Institute of Neurological Disorders and Stroke (NS038370), a Glenn Foundation Award and a Hirsch/Weill-Caulier Career Scientist Award. E.W. is supported by a Hereditary Disease Foundation Fellowship.
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Wong, E., Cuervo, A. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13, 805–811 (2010). https://doi.org/10.1038/nn.2575
This article is cited by
Different Roles of Beclin1 in the Interaction Between Glia and Neurons after Exposure to Morphine and the HIV- Trans-Activator of Transcription (Tat) Protein
Journal of Neuroimmune Pharmacology (2022)
Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex
Acta Pharmacologica Sinica (2021)
Location, location, location: subcellular protein partitioning in proteostasis and aging
Biophysical Reviews (2021)
Hypothyroidism Induces Interleukin-1-Dependent Autophagy Mechanism as a Key Mediator of Hippocampal Neuronal Apoptosis and Cognitive Decline in Postnatal Rats
Molecular Neurobiology (2021)
Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis
Journal of Inflammation (2020)