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. 2015 Jul 23;31(4):407–415. doi: 10.1007/s12264-015-1542-8

Chaperone-mediated autophagy and neurodegeneration: connections, mechanisms, and therapeutic implications

Xiaolei Liu 1,2, Sihua Huang 2,3, Xingqin Wang 2,4, Beisha Tang 1, Wenming Li 2, Zixu Mao 2,5,✉
PMCID: PMC5563713  PMID: 26206600

Abstract

Lysosomes degrade dysfunctional intracellular components via three pathways: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Unlike the other two, CMA degrades cytosolic proteins with a recognized KFERQ-like motif in lysosomes and is important for cellular homeostasis. CMA activity declines with age and is altered in neurodegenerative diseases. Its impairment leads to the accumulation of aggregated proteins, some of which may be directly tied to the pathogenic processes of neurodegenerative diseases. Its induction may accelerate the clearance of pathogenic proteins and promote cell survival, representing a potential therapeutic approach for the treatment of neurodegenerative diseases. In this review, we summarize the current findings on how CMA is involved in neurodegenerative diseases, especially in Parkinson’s disease.

Keywords: autophagy, chaperone-mediated autophagy, neurodegenerative disorder, Parkinson’s disease, risk factors, mutant proteins, therapeutic target

References

  • [1].Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717–1721. doi: 10.1126/science.290.5497.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6:463–477. doi: 10.1016/S1534-5807(04)00099-1. [DOI] [PubMed] [Google Scholar]
  • [3].Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct. 2002;27:421–429. doi: 10.1247/csf.27.421. [DOI] [PubMed] [Google Scholar]
  • [4].Ahlberg J, Glaumann H. Uptake—microautophagy—and degradation of exogenous proteins by isolated rat liver lysosomes: effects of pH, ATP, and inhibitors of proteolysis. Exp Mol Pathol. 1985;42:78–88. doi: 10.1016/0014-4800(85)90020-6. [DOI] [PubMed] [Google Scholar]
  • [5].Mortimore G, Lardeux B, Adams C. Regulation of microautophagy and basal protein turnover in rat liver. Effects of short-term starvation. J Biol Chem. 1988;263:2506–2512. [PubMed] [Google Scholar]
  • [6].Müller O, Sattler T, Flötenmeyer M, Schwarz H, Plattner H, Mayer A. Autophagic tubes vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. J Cell Biol. 2000;151:519–528. doi: 10.1083/jcb.151.3.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Dice JF. Landes Bioscience Austin, TX. 2000. Lysosomal pathways of protein degradation. [Google Scholar]
  • [8].Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant a-synuclein by chaperonemediated autophagy. Science. 2004;305:1292–1295. doi: 10.1126/science.1101738. [DOI] [PubMed] [Google Scholar]
  • [9].Kon M, Cuervo AM. Chaperone-mediated autophagy in health and disease. FEBS Lett. 2010;584:1399–1404. doi: 10.1016/j.febslet.2009.12.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, et al. IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol. 2009;187:1083–1099. doi: 10.1083/jcb.200909067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol. 2010;67:1464–1472. doi: 10.1001/archneurol.2010.198. [DOI] [PubMed] [Google Scholar]
  • [12].Koga H, Martinez-Vicente M, Arias E, Kaushik S, Sulzer D, Cuervo AM. Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease. J Neurosci. 2011;31:18492–18505. doi: 10.1523/JNEUROSCI.3219-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Li W, Yang Q, Mao Z. Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cell Mol Life Sci. 2011;68:749–763. doi: 10.1007/s00018-010-0565-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Dice JF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci. 1990;15:305–309. doi: 10.1016/0968-0004(90)90019-8. [DOI] [PubMed] [Google Scholar]
  • [15].Cuervo AM, Wong E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 2014;24:92–104. doi: 10.1038/cr.2013.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Kaushik S, Cuervo AM. Chaperone–mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22:407–417. doi: 10.1016/j.tcb.2012.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Cuervo AM, Terlecky SR, Dice JF, Knecht E. Selective binding and uptake of ribonuclease A and glyceraldehyde-3- phosphate dehydrogenase by isolated rat liver lysosomes. J Biol Chem. 1994;269:26374–26380. [PubMed] [Google Scholar]
  • [18].Majeski AE, Dice JF. Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol. 2004;36:2435–2444. doi: 10.1016/j.biocel.2004.02.013. [DOI] [PubMed] [Google Scholar]
  • [19].Orenstein SJ, Cuervo AM. Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol. 2010;21:719–726. doi: 10.1016/j.semcdb.2010.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Agarraberes FA, Dice JF. A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J Cell Sci. 2001;114:2491–2499. doi: 10.1242/jcs.114.13.2491. [DOI] [PubMed] [Google Scholar]
  • [21].Salvador N, Aguado C, Horst M, Knecht E. Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. J Biol Chem. 2000;275:27447–27456. doi: 10.1074/jbc.M001394200. [DOI] [PubMed] [Google Scholar]
  • [22].Agarraberes FA, Terlecky SR, Dice JF. An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol. 1997;137:825–834. doi: 10.1083/jcb.137.4.825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science. 1996;273:501–503. doi: 10.1126/science.273.5274.501. [DOI] [PubMed] [Google Scholar]
  • [24].Cuervo A, Dice J. Unique properties of lamp2a compared to other lamp2 isoforms. J Cell Sci. 2000;113:4441–4450. doi: 10.1242/jcs.113.24.4441. [DOI] [PubMed] [Google Scholar]
  • [25].Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM. The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol. 2008;28:5747–5763. doi: 10.1128/MCB.02070-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Dice J, Chiang H, Spencer E, Backer J. Regulation of catabolism of microinjected ribonuclease A. Identifi cation of residues 7-11 as the essential pentapeptide. J Biol Chem. 1986;261:6853–6859. [PubMed] [Google Scholar]
  • [27].Finn PF, Mesires NT, Vine M, Dice JF. Effects of small molecules on chaperone-mediated autophagy. Autophagy. 2005;1:141–145. doi: 10.4161/auto.1.3.2000. [DOI] [PubMed] [Google Scholar]
  • [28].Wing S, Chiang H, Goldberg A, Dice J. Proteins containing peptide sequences related to Lys-Phe-Glu-Arg-Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J. 1991;275:165–169. doi: 10.1042/bj2750165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Susan P, Dunn W. Starvation-induced lysosomal degradation of aldolase B requires glutamine 111 in a signal sequence for chaperone-mediated transport. J Cell Physiol. 2001;187:48–58. doi: 10.1002/1097-4652(2001)9999:9999<00::AID-JCP1050>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  • [30].Pemberton S, Madiona K, Pieri L, Kabani M, Bousset L, Melki R. Hsc70 protein interaction with soluble and fibrillar a-synuclein. J Biol Chem. 2011;286:34690–34699. doi: 10.1074/jbc.M111.261321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, et al. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010;20:143–148. doi: 10.1016/j.cub.2009.11.022. [DOI] [PubMed] [Google Scholar]
  • [32].Cuervo AM, Dice JF, Knecht E. A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins. J Biol Chem. 1997;272:5606–5615. doi: 10.1074/jbc.272.9.5606. [DOI] [PubMed] [Google Scholar]
  • [33].Gao L, She H, Li W, Zeng J, Zhu J, Jones DP, et al. Oxidation of survival factor MEF2D in neuronal death and Parkinson's disease. Antioxid Redox Signal. 2014;20:2936–2948. doi: 10.1089/ars.2013.5399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Bandyopadhyay U, Sridhar S, Kaushik S, Kiffin R, Cuervo AM. Identification of regulators of chaperone-mediated autophagy. Mol Cell. 2010;39:535–547. doi: 10.1016/j.molcel.2010.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Nedelsky NB, Todd PK, Taylor JP. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta. 2008;1782:691–699. doi: 10.1016/j.bbadis.2008.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Massey AC, Follenzi A K n R, Zhang C, Cuervo AM. Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy. 2008;4:442–456. doi: 10.4161/auto.5654. [DOI] [PubMed] [Google Scholar]
  • [37].Modgil S, Lahiri DK, Sharma VL, Anand A. Role of early life exposure and environment on neurodegeneration: implications on brain disorders. Transl Neurodegener 2014, 3. [DOI] [PMC free article] [PubMed]
  • [38].McInnes J. Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration. Transl Neurodegener. 2013;2:12. doi: 10.1186/2047-9158-2-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Rodriguez-Navarro JA, Cuervo AM. Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms. Autophagy. 2012;8:1152–1154. doi: 10.4161/auto.20649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Cuervo AM, Dice JF. Age-related decline in chaperonemediated autophagy. J Biol Chem. 2000;275:31505–31513. doi: 10.1074/jbc.M002102200. [DOI] [PubMed] [Google Scholar]
  • [41].Kiffin R, Kaushik S, Zeng M, Bandyopadhyay U, Zhang C, Massey AC, et al. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci. 2007;120:782–791. doi: 10.1242/jcs.001073. [DOI] [PubMed] [Google Scholar]
  • [42].Marin C, Aguilar E. In vivo 6-OHDA-induced neurodegeneration and nigral autophagic markers expression. Neurochem Int. 2011;58:521–526. doi: 10.1016/j.neuint.2011.01.010. [DOI] [PubMed] [Google Scholar]
  • [43].Sala G, Arosio A, Stefanoni G, Melchionda L, Riva C, Marinig D, et al. Rotenone upregulates alpha-synuclein and myocyte enhancer factor 2D independently from lysosomal degradation inhibition. BioMed Res Int 2013, 2013. [DOI] [PMC free article] [PubMed]
  • [44].Dohi E, Tanaka S, Seki T, Miyagi T, Hide I, Takahashi T, et al. Hypoxic stress activates chaperone-mediated autophagy and modulates neuronal cell survival. Neurochem Int. 2012;60:431–442. doi: 10.1016/j.neuint.2012.01.020. [DOI] [PubMed] [Google Scholar]
  • [45].Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nature medicine. 2008;14:959–965. doi: 10.1038/nm.1851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Kiffin R, Christian C, Knecht E, Cuervo AM. Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell. 2004;15:4829–4840. doi: 10.1091/mbc.E04-06-0477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Cuervo AM, Hu W, Lim B, Dice JF. IkB is a substrate for a selective pathway of lysosomal proteolysis. Mol Biol Cell. 1998;9:1995–2010. doi: 10.1091/mbc.9.8.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18:R48–R59. doi: 10.1093/hmg/ddp012. [DOI] [PubMed] [Google Scholar]
  • [49].Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identifi ed in families with Parkinson's disease. Science. 1997;276:2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  • [50].Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. Wild type a-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem. 2008;283:23542–23556. doi: 10.1074/jbc.M801992200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, et al. J Clin Invest. 2008. Dopamine-modified a-synuclein blocks chaperone-mediated autophagy. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Qi L, Zhang X-D, Wu J-C, Lin F, Wang J, Di Figlia M, et al. The role of chaperone-mediated autophagy in huntingtin degradation. PLoS One. 2012;7:e46834. doi: 10.1371/journal.pone.0046834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Mak SK, Mc Cormack AL, Manning-Bog AB, Cuervo AM, Di M DA. Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem. 2010;285:13621–13629. doi: 10.1074/jbc.M109.074617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ. The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a009357. doi: 10.1101/cshperspect.a009357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, et al. LRRK2 regulates autophagic activity and localizes to specifi c membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet. 2009;18:4022–4034. doi: 10.1093/hmg/ddp346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Orenstein SJ, Kuo S-H, Tasset I, Arias E, Koga H F-, Carasa I, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci. 2013;16:394–406. doi: 10.1038/nn.3350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [57].Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin L-S, et al. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem. 2004;279:13256–13264. doi: 10.1074/jbc.M314124200. [DOI] [PubMed] [Google Scholar]
  • [58].Kabuta T, Furuta A, Aoki S, Furuta K, Wada K. Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J Biol Chem. 2008;283:23731–23738. doi: 10.1074/jbc.M801918200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [59].Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, et al. Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron. 2003;38:33–46. doi: 10.1016/S0896-6273(03)00191-0. [DOI] [PubMed] [Google Scholar]
  • [60].Wang X, Tang X, Li M, Marshall J, Mao Z. Regulation of neuroprotective activity of myocyte-enhancer factor 2 by cAMP-protein kinase A signaling pathway in neuronal survival. J Biol Chem. 2005;280:16705–16713. doi: 10.1074/jbc.M501819200. [DOI] [PubMed] [Google Scholar]
  • [61].Tang X, Wang X, Gong X, Tong M, Park D, Xia Z, et al. Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J Neurosci. 2005;25:4823–4834. doi: 10.1523/JNEUROSCI.1331-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [62].Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, et al. Regulation of neuronal survival factor MEF2D by chaperonemediated autophagy. Science. 2009;323:124–127. doi: 10.1126/science.1166088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Irrcher I, Park DS. Parkinson’s disease: to live or die by autophagy. Sci Signaling. 2009;2:pe21–pe21. doi: 10.1126/scisignal.265pe21. [DOI] [PubMed] [Google Scholar]
  • [64].Murphy KE, Gysbers AM, Abbott SK, Spiro AS, Furuta A, Cooper A, et al. Mov Disord. 2015. Lysosomal-associated membrane protein 2 Isoforms Are Differentially Affected in Early Parkinson's Disease. [DOI] [PubMed] [Google Scholar]
  • [65].Wang Y, Martinez-Vicente M K U, Kaushik S, Wong E, Mandelkow E-M, et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009;18:4153–4170. doi: 10.1093/hmg/ddp367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [66].Khoshnan A, Ko J, Tescu S, Brundin P, Patterson PH. IKKa and IKKß regulation of DNA damage-induced cleavage of huntingtin. PLoS One. 2009;4:e5768. doi: 10.1371/journal.pone.0005768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Huang CC, Bose JK, Majumder P, Lee KH, Huang JTJ, Huang JK, et al. Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. J Cell Sci. 2014;127:3024–3038. doi: 10.1242/jcs.136150. [DOI] [PubMed] [Google Scholar]
  • [68].Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nature Chem Biol. 2011;7:9–17. doi: 10.1038/nchembio.500. [DOI] [PubMed] [Google Scholar]
  • [69].Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov. 2012;11:709–730. doi: 10.1038/nrd3802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [70].Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L. Abberant a-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One. 2009;4:e5515. doi: 10.1371/journal.pone.0005515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Xilouri M, Brekk OR, Landeck N, Pitychoutis PM, Papasilekas T P-, Daifoti Z, et al. Boosting chaperonemediated autophagy in vivo mitigates a-synuclein-induced neurodegeneration. Brain. 2013;136:2130–2146. doi: 10.1093/brain/awt131. [DOI] [PubMed] [Google Scholar]
  • [72].Xilouri M, Brekk OR, Stefanis L. Alpha-synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol. 2013;47:537–551. doi: 10.1007/s12035-012-8341-2. [DOI] [PubMed] [Google Scholar]

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