Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2014

Open Access 01-12-2014 | Review

Chaperone-mediated autophagy: roles in neurodegeneration

Authors: Gang Wang, Zixu Mao

Published in: Translational Neurodegeneration | Issue 1/2014

Login to get access

Abstract

Chaperone-mediated autophagy (CMA) selectively delivers cytosolic proteins with an exposed CMA-targeting motif to lysosomes for degradation and plays an important role in protein quality control and cellular homeostasis. A growing body of evidence supports the hypothesis that CMA dysfunction may be involved in the pathogenic process of neurodegenerative diseases. Both down-regulation and compensatory up-regulation in CMA activities have been observed in association with neurodegenerative conditions. Recent studies have revealed several new mechanisms by which CMA function may be involved in the regulation of factors critical for neuronal viability and homeostasis. Here, we summarize these recent advances in the understanding of the relationship between CMA dysfunction and neurodegeneration and discuss the therapeutic potential of targeting CMA in the treatment of neurodegenerative diseases.
Appendix
Available only for authorised users
Literature
1.
Klionsky DJ: Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007, 8(11):931-937. 10.1038/nrm2245CrossRefPubMed
2.
Kaushik S, Cuervo AM: Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 2012, 22(8):407-417. 10.1016/j.tcb.2012.05.006PubMedCentralCrossRefPubMed
3.
4.
Orenstein SJ, Cuervo AM: Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol 2010, 21(7):719-726. 10.1016/j.semcdb.2010.02.005PubMedCentralCrossRefPubMed
5.
Chiang HL, Dice JF: Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem 1988, 263(14):6797-6805.PubMed
6.
Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li Z, Xu Y, Wang G, Huang Y, Xiong Y, Guan KL, Lei QY: Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 2011, 42(6):719-730. 10.1016/j.molcel.2011.04.025CrossRefPubMed
7.
Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, Martinez-Vincente M, Arrasate M, O'Rourke JG, Khashwji H, Lukacsovich T, Zhu YZ, Lau AL, Massey A, Hayden MR, Zeitlin SO, Finkbeiner S, Green KN, LaFerla FM, Bates G, Huang L, Patterson PH, Lo DC, Cuervo AM, Marsh JL, Steffan JS: IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol 2009, 187(7):1083-1099. 10.1083/jcb.200909067PubMedCentralCrossRefPubMed
8.
Quintavalle C, Di Costanzo S, Zanca C, Tasset I, Fraldi A, Incoronato M, Mirabelli P, Monti M, Ballabio A, Pucci P, Cuervo AM, Condorelli G: Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells. J Cell Physiol 2014, 229(10):1359-1368. 10.1002/jcp.24569PubMedCentralCrossRefPubMed
9.
Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z: Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 2009, 323(5910):124-127. 10.1126/science.1166088PubMedCentralCrossRefPubMed
10.
Kiffin R, Christian C, Knecht E, Cuervo AM: Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 2004, 15(11):4829-4840. 10.1091/mbc.E04-06-0477PubMedCentralCrossRefPubMed
11.
12.
Kubota H: Quality control against misfolded proteins in the cytosol: a network for cell survival. J Biochem 2009, 146(5):609-616. 10.1093/jb/mvp139CrossRefPubMed
13.
Sooparb S, Price SR, Shaoguang J, Franch HA: Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus. Kidney Int 2004, 65(6):2135-2144. 10.1111/j.1523-1755.2004.00639.xCrossRefPubMed
14.
Pemberton S, Madiona K, Pieri L, Kabani M, Bousset L, Melki R: Hsc70 protein interaction with soluble and fibrillar alpha-synuclein. J Biol Chem 2011, 286(40):34690-34699. 10.1074/jbc.M111.261321PubMedCentralCrossRefPubMed
15.
Li W, Yang Q, Mao Z: Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cellular and molecular life sciences: CMLS 2011, 68(5):749-763. 10.1007/s00018-010-0565-6CrossRefPubMed
16.
Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L: Microautophagy of cytosolic proteins by late endosomes. Dev Cell 2011, 20(1):131-139. 10.1016/j.devcel.2010.12.003PubMedCentralCrossRefPubMed
17.
Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J: Chaperone-assisted selective autophagy is essential for muscle maintenance. Current biology: CB 2010, 20(2):143-148. 10.1016/j.cub.2009.11.022CrossRefPubMed
18.
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(9):5606-5615. 10.1074/jbc.272.9.5606CrossRefPubMed
19.
Cuervo AM, Knecht E, Terlecky SR, Dice JF: Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am J Physiol 1995, 269(5 Pt 1):C1200-C1208.PubMed
20.
Cuervo AM, Dice JF: Unique properties of lamp2a compared to other lamp2 isoforms. J Cell Sci 2000, 113(Pt 24):4441-4450.PubMed
21.
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(18):5747-5763. 10.1128/MCB.02070-07PubMedCentralCrossRefPubMed
22.
Eskelinen EL, Schmidt CK, Neu S, Willenborg M, Fuertes G, Salvador N, Tanaka Y, Lüllmann-Rauch R, Hartmann D, Heeren J, von Figura K, Knecht E, Saftig P: Disturbed cholesterol traffic but normal proteolytic function in LAMP-1/LAMP-2 double-deficient fibroblasts. Mol Biol Cell 2004, 15(7):3132-3145. 10.1091/mbc.E04-02-0103PubMedCentralCrossRefPubMed
23.
Appelqvist H, Waster P, Kagedal K, Ollinger K: The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 2013, 5(4):214-226. 10.1093/jmcb/mjt022CrossRefPubMed
24.
Eskelinen EL, Illert AL, Tanaka Y, Schwarzmann G, Blanz J, Von Figura K, Saftig P: Role of LAMP-2 in lysosome biogenesis and autophagy. Mol Biol Cell 2002, 13(9):3355-3368. 10.1091/mbc.E02-02-0114PubMedCentralCrossRefPubMed
25.
Saftig P, Klumperman J: Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 2009, 10(9):623-635. 10.1038/nrm2745CrossRefPubMed
26.
Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, Ballabio A: Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 2011, 20(19):3852-3866. 10.1093/hmg/ddr306CrossRefPubMed
27.
Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M: Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Neuroscience 2013, 250: 8-19.CrossRefPubMed
28.
Pena-Llopis S, Brugarolas J: TFEB, a novel mTORC1 effector implicated in lysosome biogenesis, endocytosis and autophagy. Cell Cycle 2011, 10(23):3987-3988. 10.4161/cc.10.23.18251PubMedCentralCrossRefPubMed
29.
Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A: TFEB links autophagy to lysosomal biogenesis. Sci 2011, 332(6036):1429-1433. 10.1126/science.1204592CrossRef
30.
Tong J, Yan X, Yu L: The late stage of autophagy: cellular events and molecular regulation. Protein Cell 2010, 1(10):907-915. 10.1007/s13238-010-0121-zCrossRefPubMed
31.
Yang Z, Huang J, Geng J, Nair U, Klionsky DJ: Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol Biol Cell 2006, 17(12):5094-5104. 10.1091/mbc.E06-06-0479PubMedCentralCrossRefPubMed
32.
Yang Z, Klionsky DJ: Permeases recycle amino acids resulting from autophagy. Autophagy 2007, 3(2):149-150. 10.4161/auto.3631CrossRefPubMed
33.
Bandyopadhyay U, Sridhar S, Kaushik S, Kiffin R, Cuervo AM: Identification of regulators of chaperone-mediated autophagy. Mol Cell 2010, 39(4):535-547. 10.1016/j.molcel.2010.08.004PubMedCentralCrossRefPubMed
34.
35.
Todde V, Veenhuis M, van der Klei IJ: Autophagy: principles and significance in health and disease. Biochim Biophys Acta 2009, 1792(1):3-13. 10.1016/j.bbadis.2008.10.016CrossRefPubMed
36.
Yabu T, Imamura S, Mohammed MS, Touhata K, Minami T, Terayama M, Yamashita M: Differential gene expression of HSC70/HSP70 in yellowtail cells in response to chaperone-mediated autophagy. FEBS J 2011, 278(4):673-685. 10.1111/j.1742-4658.2010.07989.xCrossRefPubMed
37.
Balch WE, Morimoto RI, Dillin A, Kelly JW: Adapting Proteostasis for Disease Intervention. Science 2008, 319(5865):916-919. 10.1126/science.1141448CrossRefPubMed
38.
Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM: Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A 2006, 103(15):5805-5810. 10.1073/pnas.0507436103PubMedCentralCrossRefPubMed
39.
Kaushik S, Massey AC, Mizushima N, Cuervo AM: Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol Biol Cell 2008, 19(5):2179-2192. 10.1091/mbc.E07-11-1155PubMedCentralCrossRefPubMed
40.
Massey AC, Follenzi A, Kiffin R, Zhang C, Cuervo AM: Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy 2008, 4(4):442-456. 10.4161/auto.5654CrossRefPubMed
41.
Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC: Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 2009, 33(4):517-527. 10.1016/j.molcel.2009.01.021PubMedCentralCrossRefPubMed
42.
Cuervo AM, Dice JF: Age-related decline in chaperone-mediated autophagy. J Biol Chem 2000, 275(40):31505-31513. 10.1074/jbc.M002102200CrossRefPubMed
43.
Gao L, She H, Li W, Zeng J, Zhu J, Jones DP, Mao Z, Gao G, Yang Q: Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson’s Disease. Antioxid Redox Signal 2014, 20(18):2936-2948. 10.1089/ars.2013.5399PubMedCentralCrossRefPubMed
44.
Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, Schapira AH: Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 2010, 67(12):1464-1472.CrossRefPubMed
45.
Koga H, Martinez-Vicente M, Arias E, Kaushik S, Sulzer D, Cuervo AM: Constitutive upregulation of chaperone-mediated autophagy in Huntington’s disease. The J Neurosci: Official J Soc Neurosci 2011, 31(50):18492-18505. 10.1523/JNEUROSCI.3219-11.2011CrossRef
46.
Modgil S, Lahiri DK, Sharma VL, Anand A: Role of early life exposure and environment on neurodegeneration: implications on brain disorders. Transl Neurodegeneration 2014, 3: 9. 10.1186/2047-9158-3-9CrossRef
47.
McInnes J: Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration. Transl Neurodegeneration 2013, 2(1):12. 10.1186/2047-9158-2-12CrossRef
48.
Marin C, Aguilar E: In vivo 6-OHDA-induced neurodegeneration and nigral autophagic markers expression. Neurochem Int 2011, 58(4):521-526. 10.1016/j.neuint.2011.01.010CrossRefPubMed
49.
Dohi E, Tanaka S, Seki T, Miyagi T, Hide I, Takahashi T, Matsumoto M, Sakai N: Hypoxic stress activates chaperone-mediated autophagy and modulates neuronal cell survival. Neurochem Int 2012, 60(4):431-442. 10.1016/j.neuint.2012.01.020CrossRefPubMed
50.
Sala G, Arosio A, Stefanoni G, Melchionda L, Riva C, Marinig D, Brighina L, Ferrarese C: Rotenone upregulates alpha-synuclein and myocyte enhancer factor 2D independently from lysosomal degradation inhibition. BioMed Res Int 2013, 2013: 846725.PubMedCentralCrossRefPubMed
51.
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D: Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Sci 2004, 305(5688):1292-1295. 10.1126/science.1101738CrossRef
52.
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(35):23731-23738. 10.1074/jbc.M801918200PubMedCentralCrossRefPubMed
53.
Wang Y, Kruger U, Mandelkow E, Mandelkow EM: Generation of tau aggregates and clearance by autophagy in an inducible cell model of tauopathy. Neurodegener Dis 2010, 7(1–3):103-107.CrossRefPubMed
54.
Rodriguez-Navarro JA, Cuervo AM: Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms. Autophagy 2012, 8(7):1152-1154.PubMedCentralCrossRefPubMed
55.
Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM: Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 2008, 118(2):777-788.PubMedCentralPubMed
56.
Qi L, Zhang XD: Role of chaperone-mediated autophagy in degrading Huntington’s disease-associated huntingtin protein. Acta Biochim Biophys Sin 2014, 46(2):83-91. 10.1093/abbs/gmt133CrossRefPubMed
57.
Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E: Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 2009, 18(21):4153-4170. 10.1093/hmg/ddp367PubMedCentralCrossRefPubMed
58.
Kabuta T, Wada K: Insights into links between familial and sporadic Parkinson’s disease: physical relationship between UCH-L1 variants and chaperone-mediated autophagy. Autophagy 2008, 4(6):827-829. 10.4161/auto.6560CrossRefPubMed
59.
Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM: Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 2013, 16(4):394-406. 10.1038/nn.3350PubMedCentralCrossRefPubMed
60.
Pan PY, Yue Z: Genetic causes of Parkinson’s disease and their links to autophagy regulation. Parkinsonism Relat Disord 2014, 20(Suppl 1):S154-S157.CrossRefPubMed
61.
Liu H, Wang P, Song W, Sun X: Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB J: Official publication Fed Am Soc Exp Biology 2009, 23(10):3383-3392. 10.1096/fj.09-134296CrossRef
62.
Massey AC, Zhang C, Cuervo AM: Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 2006, 73: 205-235.CrossRefPubMed
63.
64.
Sotelo J, Briceno E, Lopez-Gonzalez MA: Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2006, 144(5):337-343. 10.7326/0003-4819-144-5-200603070-00008CrossRefPubMed
65.
Kimura T, Takabatake Y, Takahashi A, Isaka Y: Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res 2013, 73(1):3-7. 10.1158/0008-5472.CAN-12-2464CrossRefPubMed
66.
Sala G, Stefanoni G, Arosio A, Riva C, Melchionda L, Saracchi E, Fermi S, Brighina L, Ferrarese C: Reduced expression of the chaperone-mediated autophagy carrier hsc70 protein in lymphomonocytes of patients with Parkinson’s disease. Brain Res 2014, 1546: 46-52.CrossRefPubMed
Metadata
Title
Chaperone-mediated autophagy: roles in neurodegeneration
Authors
Gang Wang
Zixu Mao
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2014
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/2047-9158-3-20

Other articles of this Issue 1/2014

Translational Neurodegeneration 1/2014 Go to the issue

Editorial

Expression of concern: measles-mumps-rubella vaccination timing and autism among young African American boys: a reanalysis of CDC data

Review

Considerations on the role of environmental toxins in idiopathic Parkinson’s disease pathophysiology

Review

Regulation of Myelination in the Central Nervous System by Nuclear Lamin B1 and Non-coding RNAs

Review

Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders

Short report

In silico analysis of regulatory networks underlines the role of miR-10b-5p and its target BDNF in huntington’s disease

Research

Prevalence of wearing-off and dyskinesia among the patients with Parkinson’s disease on levodopa therapy: a multi-center registry survey in mainland China