Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Abstract
Aberrant α-synuclein degradation is implicated in Parkinson's disease pathogenesis because the protein accumulates in the Lewy inclusion bodies associated with the disease. Little is known, however, about the pathways by which wild-type α-synuclein is normally degraded. We found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic A53T and A30P α-synuclein mutants bound to the receptor for this pathway on the lysosomal membrane, but appeared to act as uptake blockers, inhibiting both their own degradation and that of other substrates. These findings may underlie the toxic gain-of-function by the mutants.
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Previous studies suggest α-synuclein is degraded by macroautophagy, chaperone-mediated autophagy, and the proteasome.
“Previous studies suggest that α-synuclein is degraded by macroautophagy, chaperone-mediated autophagy, and the proteasome20–23.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [20]
Inhibition of a particular degradative pathway is typically accompanied by an increase in a separate pathway as the cell attempts to compensate for the loss of degradative capacity.
“Finally, inhibition of a particular degradative pathway is typically accompanied by an increase in a separate pathway as the cell attempts to compensate for the loss of degradative capacity.158,478,493”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [493]
Animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.
“and animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.40–42”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [42]
Dopamine-modified α-synuclein blocks chaperone-mediated autophagy, which induces abnormal intracellular accumulation of α-synuclein in PD.
“dopamine-modified α-synuclein blocks chaperone-mediated autophagy [109,110], which induces abnormal intracellular accumulation α-synuclein in PD [120].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [109]
Early evidence suggested roles for CMA and macroautophagy in degrading SNCA/α-synuclein.
“Early evidence suggested roles for CMA and macroautophagy in degrading SNCA/α‐synuclein (Webb et al, 2003; Cuervo et al, 2004).”
From Autophagy in major human diseases (2021) · cites this paper as Cuervo et al, 2004
High expression of wild-type SNCA/α-synuclein, mutations or unwanted posttranslational modifications on this protein (such as formation of dopamine adducts) is toxic to CMA by preventing multimerization of LAMP2A and subsequent lysosomal internalization of cargo proteins.
“High expression of wild‐type SNCA/α‐synuclein, mutations or unwanted posttranslational modifications on this protein (such as formation of dopamine adducts) is toxic to CMA by preventing multimerization of LAMP2A and subsequent lysosomal internalization of cargo proteins (Cuervo et al, 2004; Martinez‐Vicente et al, 2008).”
From Autophagy in major human diseases (2021) · cites this paper as Cuervo et al, 2004
The extent to which autophagy contributes to synuclein degradation depends on the presence of mutations.
“The protein catabolic pathways that regulate synuclein degradation have been discussed by multiple authors4,16,17, and the extent to which autophagy contributes to synuclein degradation depends on the presence of mutations18.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [18]
Cites
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469 · see citing works
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction
Glickman, M. H., & Ciechanover, A. J. (2002) · Physiological Reviews · doi:10.1152/physrev.00027.2001 · Cited by 4,216 · see citing works
Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W.-H., Castillo, P. E., Shinsky, N., Verdugo, J. M. G., Armanini, M., Ryan, A., et al. (2000) · Neuron · doi:10.1016/s0896-6273(00)80886-7 · Cited by 1,722 · see citing works
Self-citationα-Synuclein Is Degraded by Both Autophagy and the Proteasome
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300227200 · Cited by 1,429 · see citing works
A Receptor for the Selective Uptake and Degradation of Proteins by Lysosomes
Cuervo, A. M., & Dice, J. F. (1996) · Science · doi:10.1126/science.273.5274.501 · Cited by 979 · see citing works
Self-citationAutophagy: in sickness and in health
Cuervo, A. M. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.12.002 · Cited by 816 · see citing works
Self-citationPeptide sequences that target cytosolic proteins for lysosomal proteolysis
Dice, J. F. (1990) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(90)90019-8 · Cited by 755 · see citing works
Volles, M. J., Lee, S., Rochet, J., Shtilerman, M. D., Ding, T. T., Kessler, J. C., & Lansbury, P. T. (2001) · Biochemistry · doi:10.1021/bi0102398 · Cited by 682 · see citing works
Self-citationStefanis, L., Larsen, K. E., Rideout, H. J., Sulzer, D. L., & Greene, L. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-24-09549.2001 · Cited by 569 · see citing works
Self-citationFailure of the ubiquitin-proteasome system in Parkinson’s disease
McNaught, K. S. P., Olanow, C. W., Halliwell, B., Isacson, O., & Jenner, P. (2001) · Nature Reviews Neuroscience · doi:10.1038/35086067 · Cited by 519 · see citing works
Grantcharova, V., Alm, E. J., Baker, D. A., & Horwich, A. L. (2001) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(00)00176-7 · Cited by 474 · see citing works
Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway
Lee, H.-J., Khoshaghideh, F., Patel, S., & Lee, S.-J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3809-03.2004 · Cited by 445 · see citing works
Induction of α-Synuclein Aggregation by Intracellular Nitrative Insult
Paxinou, E., Chen, Q., Weisse, M., Giasson, B. I., Norris, E. H., Rueter, S. M., Trojanowski, J. Q., Lee, V. M. ‐., & Ischiropoulos, H. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-20-08053.2001 · Cited by 440 · see citing works
Degradation of α-Synuclein by Proteasome
Bennett, M. C., Bishop, J. F., Leng, Y., Chock, P. B., Chase, T. N., & Mouradian, M. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.48.33855 · Cited by 417 · see citing works
Tofaris, G. K., Layfield, R., & Spillantini, M. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03115-5 · Cited by 363 · see citing works
Cuervo, A. M., Dice, J. F., & Knecht, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.9.5606 · Cited by 299 · see citing works
Self-citationRideout, H. J., Larsen, K. E., Sulzer, D. L., & Stefanis, L. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00474.x · Cited by 274 · see citing works
Self-citationAutophagy in neurons: a review.
Larsen, K. E., & Sulzer, D. L. (2002) · PubMed · doi:10.14670/hh-17.897 · Cited by 242 · see citing works
Self-citationSalvador-Montoliu, N., Aguado, C., Horst, M., & Knecht, E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001394200 · Cited by 238 · see citing works
Lysosomes, a meeting point of proteins, chaperones, and proteases
Cuervo, A. M., & Dice, J. F. (1997) · Journal of Molecular Medicine · doi:10.1007/s001090050185 · Cited by 202 · see citing works
Self-citationFuertes, G., de Llano, J. J. M., Villarroya, A., Rivett, A. J., & Knecht, E. (2003) · Biochemical Journal · doi:10.1042/bj20030282 · Cited by 162 · see citing works
Genetics of Parkinson's disease
Nussbaum, R. L. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.10.1687 · Cited by 155 · see citing works
Cuervo, A. M., Terlecky, S. R., Dice, J. F., & Knecht, E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47204-3 · Cited by 138 · see citing works
Self-citationRideout, H. J., & Stefanis, L. (2002) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2002.1173 · Cited by 128 · see citing works
Self-citationAncolio, K., da Costa, C. A., Uéda, K., & Checler, F. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01049-1 · Cited by 110 · see citing works
Wilson, C., Murphy, D. D., Giasson, B. I., Zhang, B., Trojanowski, J. Q., & Lee, V. M. ‐. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403061 · Cited by 106 · see citing works
Lysosomal Pathways of Protein Degradation
Dice, J. F. (2000) · CRC Press eBooks · doi:10.1201/9781498713054 · Cited by 71 · see citing works
Flagged first, then by citations
1 of the 28 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Autophagy fights disease through cellular self-digestion
Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008) · Nature · doi:10.1038/nature06639 · Cited by 6,452 · see citing works
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · see citing works
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
Klionsky, D. J., Abeliovich, H., Agostinis, P., Agrawal, D. K., Aliev, G., Askew, D. S., Baba, M., Baehrecke, E. H., Bahr, B. A., Ballabio, A., et al. (2008) · Autophagy · doi:10.4161/auto.5338 · Cited by 2,230 · see citing works
Self-citationThe role of autophagy in neurodegenerative disease
Nixon, R. A. (2013) · Nature Medicine · doi:10.1038/nm.3232 · Cited by 2,059 · see citing works
Signals from the lysosome: a control centre for cellular clearance and energy metabolism
Settembre, C., Fraldi, A., Medina, D. L., & Ballabio, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3565 · Cited by 1,689 · see citing works
Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function
Säftig, P., & Klumperman, J. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2745 · Cited by 1,702 · see citing works
Autophagy in cell death: an innocent convict?
Levine, B. (2005) · Journal of Clinical Investigation · doi:10.1172/jci26390 · Cited by 1,671 · see citing works
The roles of intracellular protein-degradation pathways in neurodegeneration
Rubinsztein, D. C. (2006) · Nature · doi:10.1038/nature05291 · Cited by 1,625 · see citing works
“In assays in vitro using isolated lysosomes, the pathogenic A53T and A30P α-synuclein mutant proteins were shown to bind to the CMA-pathway receptor on the lysosomal membrane, but seem to act as uptake blockers, inhibiting both their own degradation and that of other substrate”
BackgroundThe many faces of α-synuclein: from structure and toxicity to therapeutic target
Lashuel, H. A., Overk, C., Oueslati, A., & Masliah, E. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3406 · Cited by 1,623 · see citing works
Autophagy in major human diseases
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585 · see citing works
Self-citation-Synuclein in Parkinson's Disease
Stefanis, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009399 · Cited by 1,446 · see citing works
“Interestingly, the main proteins involved in CMA, Lamp2a and Hsc70, are diminished in PD brains (Alvarez-Erviti et al. 2010).”
BackgroundInfluentialSelf-citationThe Biology of Proteostasis in Aging and Disease
Labbadia, J., & Morimoto, R. I. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-033955 · Cited by 1,472 · see citing works
The coming of age of chaperone-mediated autophagy
Kaushik, S., & Cuervo, A. M. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0001-6 · Cited by 1,422 · see citing works
Self-citationGenetics of Parkinson's DiseasePreprint
Klein, C., & Westenberger, A. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a008888 · Cited by 1,370 · see citing works
“Wild-type a-synuclein is selectively translocated into lysosomes for degradation (Cuervo et al. 2004), and inhibitors of the lysosomal enzyme b-glucocerebrosidase, mutations in which represent a wellvalidated risk factor for PD, modulate a-synuclein levels (Manning-Bog et al. 2009).”
BackgroundMOLECULAR PATHOPHYSIOLOGY OF PARKINSON'S DISEASE
Moore, D. J., West, A. B., Dawson, V. L., & Dawson, T. M. (2005) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.28.061604.135718 · Cited by 1,274 · see citing works
“2001b), impaired chaperone-mediated autophagy (Cuervo et al. 2004), and increased sensitivity to oxidative stress (Ko et al.”
BackgroundRamirez, A., Heimbach, A., Gründemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., et al. (2006) · Nature Genetics · doi:10.1038/ng1884 · Cited by 1,208 · see citing works
Lee, J.-H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., Wolfe, D. M., Martinez-Vicente, M., Massey, A. C., Sovak, G., et al. (2010) · Cell · doi:10.1016/j.cell.2010.05.008 · Cited by 1,212 · see citing works
“…vacuoles (AVs), the general term for intermediate vesicular compartments in the process of autophagy, accumulate in several neurodegenerative diseases (Cuervo et al., 2004; Nixon et al., 2005; Ravikumar et al., 2004) but autophagy pathology in Alzheimer’s disease (AD) is exceptionally robust.”
Self-citationMulti-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Boland, B., Kumar, A., Lee, S., Platt, F. M., Wegiel, J., Yu, W. H., & Nixon, R. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0800-08.2008 · Cited by 1,119 · see citing works
“Dysfunction within either of two proteolytic pathways, involved in clearing abnormal or obsolete cellular proteins, the ubiquitin– proteasome system (UPS) and the autophagic–lysosomal system, have been increasingly implicated in proteinopathies of Alzheimer’s disease (AD), Huntington’s disease, Parkinson’s disease, an…”
BackgroundSelective neuronal vulnerability in Parkinson disease
Surmeier, D. J., Obeso, J. A., & Halliday, G. M. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.178 · Cited by 1,120 · see citing works
Ageing and neuronal vulnerability
Mattson, M. P., & Magnus, T. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn1886 · Cited by 1,075 · see citing works
“Such protein aggregates might arise, in part, as a consequence of impaired proteasomal and/or autophagic removal of the (oxidatively) damaged protein”
BackgroundAutophagy and apoptosis dysfunction in neurodegenerative disorders
Ghavami, S., Shojaei, S., Yeganeh, B., Ande, S. R., Jangamreddy, J. R., Mehrpour, M., Christoffersson, J., Chaabane, W., Moghadam, A. R., Kashani, H. H., et al. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.10.004 · Cited by 1,039 · see citing works
“…mutated a-syn (Vogiatzi et al., 2008) CMA degrades wild-type a-syn (Cuervo et al., 2004; Vogiatzi et al., 2008) CMA is inhibited by mutated a-syn (Cuervo et al., 2004) CMA activity is reduced in the brain of PD patient (Alvarez-Erviti et al., 2010) Rapamycin (Dehay et al., 2010; Mendelsohn and…”
InfluentialModulation of neurodegeneration by molecular chaperones
Muchowski, P. J., & Wacker, J. L. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1587 · Cited by 1,021 · see citing works
“It was recently suggested that mutant α-synuclein might antagonize the receptor that is involved in chaperone-mediated autophagy, thereby enhancing the accumulation of toxic misfolded proteins and resulting in cellular dysfunctio”
BackgroundSarkar, S., Davies, J. E., Huang, Z., Tunnacliffe, A., & Rubinsztein, D. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609532200 · Cited by 1,142 · see citing works
Lithium induces autophagy by inhibiting inositol monophosphatase
Sarkar, S., Floto, R. A., Berger, Z., Imarisio, S., Cordenier, A., Pasco, M., Cook, L. J., & Rubinsztein, D. C. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200504035 · Cited by 985 · see citing works
“Unlike wild-type -synuclein, the clearance of these mutant forms is retarded when autophagy is inhibited (Webb et al., 2003; Cuervo et al., 2004).”
BackgroundInfluentialMacroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease
Yu, W. H., Cuervo, A. M., Kumar, A., Peterhoff, C. M., Schmidt, S. D., Lee, J.-H., Mohan, P. S., Mercken, M., Farmery, M. R., Tjernberg, L. O., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200505082 · Cited by 967 · see citing works
“Moreover, macroautophagy is involved in degrading mutated and aggregated proteins that are implicated in neurodegenerative diseases, including Parkinson’s (Cuervo et al., 2004) and Huntington’s disease (Ravikumar et al., 2004).”
BackgroundInfluentialSelf-citationStructure and Dynamics of Micelle-bound Human α-Synuclein
Ulmer, T. S., Bax, A., Cole, N. B., & Nussbaum, R. L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m411805200 · Cited by 966 · see citing works
Endoplasmic Reticulum Stress Triggers Autophagy
Yorimitsu, T., Nair, U., Yang, Z., & Klionsky, D. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607007200 · Cited by 941 · see citing works
Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies
Ciechanover, A., & Kwon, Y. T. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.117 · Cited by 898 · see citing works
The lysosome as a cellular centre for signalling, metabolism and quality control
Lawrence, R. E., & Zoncu, R. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0244-7 · Cited by 920 · see citing works
α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies
Wong, Y. C., & Krainc, D. (2017) · Nature Medicine · doi:10.1038/nm.4269 · Cited by 897 · see citing works
T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Sulzer, D., Alcalay, R. N., Garretti, F., Cote, L., Kanter, E., Agin-Liebes, J., Liong, C., McMurtrey, C., Hildebrand, W. H., Mao, X., et al. (2017) · Nature · doi:10.1038/nature22815 · Cited by 866 · see citing works
Self-citationDirect Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
Cremades, N., Cohen, S. I. A., Deas, E., Abramov, A. Y., Chen, A. Y., Orte, Á., Sandal, M., Clarke, R. W., Dunne, P., Aprile, F. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.037 · Cited by 901 · see citing works
“It is interesting to note in this regard that this slow structural conversion is on the same timescale as the half-life for aS turnover in vivo reported previously (Cuervo et al., 2004; Okochi et al., 2000).”
Autophagy gone awry in neurodegenerative diseases
Wong, E. S. P., & Cuervo, A. M. (2010) · Nature Neuroscience · doi:10.1038/nn.2575 · Cited by 883 · see citing works
“Cross-talk between these pathways is of particular interest in neurodegeneration because primary blockage of CMA has been identified in Parkinson's disease models and certain tauopathie”
Self-citationCargo recognition failure is responsible for inefficient autophagy in Huntington’s disease
Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., de Vries, R., Arias, E., Harris, S., Sulzer, D., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2528 · Cited by 885 · see citing works
“or in models expressing pathogenic forms of α-synuclei”
BackgroundSelf-citationBendor, J. T., Logan, T. P., & Edwards, R. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.09.004 · Cited by 825 · see citing works
Compromised autophagy and neurodegenerative diseases
Menzies, F. M., Fleming, A., & Rubinsztein, D. C. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3961 · Cited by 851 · see citing works
Chaperone-mediated autophagy: a unique way to enter the lysosome world
Kaushik, S., & Cuervo, A. M. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.05.006 · Cited by 850 · see citing works
Self-citationα-Synuclein impairs macroautophagy: implications for Parkinson’s disease
Winslow, A. R., Chen, C.-W., Corrochano, S., Acevedo-Arozena, A., Gordon, D. E., Peden, A. A., Lichtenberg, M., Menzies, F. M., Ravikumar, B., Imarisio, S., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201003122 · Cited by 825 · see citing works
“Vol. 190 No. 6 1023–1037 www.jcb.org/cgi/doi/10.1083/jcb.201003122 JCB 1023 Correspondence to David C. Rubinsztein: dcr1000@hermes.cam.ac.uk Abbreviations used in this paper: ANOVA, analysis of variance; CMA, chaperonemediated autophagy; HD, Huntington’s disease; PD, Parkinson’s disease; PI(3)P, phosphatidylinositol-3…”
InfluentialChaperone-mediated autophagy: roles in disease and aging
Cuervo, A. M., & Wong, E. S. P. (2013) · Cell Research · doi:10.1038/cr.2013.153 · Cited by 850 · see citing works
Self-citationGenetic Animal Models of Parkinson's Disease
Dawson, T. M., Ko, H. S., & Dawson, V. L. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.034 · Cited by 825 · see citing works
“…a-synuclein seems to occur through mitochondrial dysfunction and proteasomal and lysosomal impairments and disruption of ER-Golgi trafficking, which set forth feed-forward mechanisms of further injury (Figure 1) (Cooper et al., 2006; Cuervo et al., 2004; Martin et al., 2006; Tanaka et al., 2001).”
Novel targets for Huntington's disease in an mTOR-independent autophagy pathway
Williams, A., Sarkar, S., Cuddon, P., Ttofi, E. K., Saiki, S., Siddiqi, F. H., Jahreiss, L., Fleming, A., Pask, D., Goldsmith, P., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.79 · Cited by 800 · see citing works
“Our primary screen assayed clearance of A30P α-synuclein, a known autophagy substrate, in stable inducible PC12 cell”
Autophagy and aging: The importance of maintaining "clean" cells
Cuervo, A. M., Bergamini, E., Brunk, U. T., Dröge, W., Ffrench, M., & Terman, A. (2005) · Autophagy · doi:10.4161/auto.1.3.2017 · Cited by 792 · see citing works
Self-citationTFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
Decressac, M., Mattsson, B., Weikop, P., Lundblad, M., Jakobsson, J., & Björklund, A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305623110 · Cited by 753 · see citing works
Pathogenic Lysosomal Depletion in Parkinson's Disease
Dehay, B., Bové, J., Rodríguez-Muela, N., Perier, C., Recasens, A., Boya, P., & Vila, M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1920-10.2010 · Cited by 825 · see citing works
“While alterations in CMA have been linked to PD because of the ability of mutant and posttranslationally modified -synuclein to block CMA in vitro (Cuervo et al., 2004; Martinez-Vicente et al., 2008), macroautophagy dysregulation is increasingly recognized as a potential pathogenic factor in…”
BackgroundAlpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease
Rocha, E. M., Miranda, B. D., & Sanders, L. H. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.04.004 · Cited by 769 · see citing works
“In particular, (but not at the exclusion of other ALP pathways) chaperonemediated autophagy (CMA) has been proposed to effect α-synuclein turnover and metabolism.”
InfluentialLysosomes as a therapeutic target
Bonam, S. R., Wang, F., & Muller, S. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0036-1 · Cited by 764 · see citing works
Missing pieces in the Parkinson's disease puzzle
Obeso, J. A., Rodríguez‐Oroz, M., Goetz, C. G., Marin, C. A., Kordower, J. H., Rodrı́guez, M., Hirsch, É. C., Farrer, M. J., Schapira, A. H. V., & Halliday, G. M. (2010) · Nature Medicine · doi:10.1038/nm.2165 · Cited by 737 · see citing works
“Mutations in and overexpression of α-synuclein seem to be especially toxic to dopaminergic neurons, as dopamine-synuclein adducts may inhibit chaperone-mediated autophag”
BackgroundThe role of protein clearance mechanisms in organismal ageing and age-related diseases
Vı́lchez, D., Sáez, I., & Dillin, A. G. (2014) · Nature Communications · doi:10.1038/ncomms6659 · Cited by 684 · see citing works
Mitochondrial dysfunction in Parkinson's disease
Winklhofer, K. F., & Haass, C. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.08.013 · Cited by 688 · see citing works
“degradation [270–275], Golgi fragmentation [276], sequestration of anti-apoptotic proteins into aggregates [277], and the formation of”
Vogiatzi, T., Xilouri, M., Vekrellis, K., & Stefanis, L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801992200 · Cited by 683 · see citing works
Self-citationAutophagy, amyloidogenesis and Alzheimer disease
Nixon, R. A. (2007) · Journal of Cell Science · doi:10.1242/jcs.019265 · Cited by 749 · see citing works
“Notably APP and synuclein, a protein implicated in Parkinson disease, contain this targeting sequence (Massey et al., 2004), and impaired CMA-mediated degradation contributes to accumulation of mutant -synuclein in the disease (Cuervo et al., 2004).”
BackgroundDiagnosis and treatment of Parkinson disease: molecules to medicine
Savitt, J. M. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29178 · Cited by 649 · see citing works
Selective autophagy: ubiquitin-mediated recognition and beyond
Kraft, C., Peter, M., & Hofmann, K. (2010) · Nature Cell Biology · doi:10.1038/ncb0910-836 · Cited by 639 · see citing works
Dopamine-modified α-synuclein blocks chaperone-mediated autophagy
Martínez‐Vicente, M., Tallóczy, Z., Kaushik, S., Massey, A. C., Mazzulli, J. R., Mosharov, E. V., Hodara, R., Fredenburg, R. A., Wu, D.-C., Follenzi, A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32806 · Cited by 633 · see citing works
Self-citationTau fragmentation, aggregation and clearance: the dual role of lysosomal processing
Wang, Y., Martinez-Vicente, M., Krüger, U., Kaushik, S., Wong, E., Mandelkow, E.-M., Cuervo, A. M., & Mandelkow, E. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp367 · Cited by 617 · see citing works
What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease
Corti, O., Lesage, S., & Brice, A. (2011) · Physiological Reviews · doi:10.1152/physrev.00022.2010 · Cited by 610 · see citing works
Lv, L., Dong, L., Zhao, D., Lin, R., Chu, Y., Zhang, H., Zha, Z., Liu, Y., Li, Z., Xu, Y., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.025 · Cited by 605 · see citing works
“Both lysosome binding and uptake assays were carried out as described previously (Cuervo et al., 2004).”
MethodWhat is the role of protein aggregation in neurodegeneration?
Ross, C. A., & Poirier, M. A. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1742 · Cited by 604 · see citing works
Understanding Dopaminergic Cell Death Pathways in Parkinson Disease
Michel, P. P., Hirsch, É. C., & Hunot, S. (2016) · Neuron · doi:10.1016/j.neuron.2016.03.038 · Cited by 594 · see citing works
“Besides macroautophagy, chaperone-mediated autophagy (CMA) has also been implicated in PD (Cuervo et al., 2014) (Figure 1).”
InfluentialBasic mechanisms of neurodegeneration: a critical update
Jellinger, K. A. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01010.x · Cited by 608 · see citing works
Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R., Adame, A., Wyss-Coray, T., & Masliah, E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4390-09.2009 · Cited by 595 · see citing works
“Moreover, studies have shown that mutant -syn inhibits CMA and triggers increased macroautophagy and lysosomal dysfunction independent of CMA (Cuervo et al., 2004; Xilouri et al., 2009).”
BackgroundInfluentialInterplay of LRRK2 with chaperone-mediated autophagy
Orenstein, S. J., Kuo, S.-H., Tasset, I., Arias, E., Koga, H., Fernandez-Carasa, I., Cortes, E., Honig, L. S., Dauer, W., Consiglio, A., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3350 · Cited by 588 · see citing works
Self-citationThe link between the GBA gene and parkinsonism
Sidransky, E., & Lopez, G. J. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70190-4 · Cited by 575 · see citing works
Cell Biology and Pathophysiology of α-SynucleinPreprint
Burré, J., Sharma, M., & Südhof, T. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 576 · see citing works
Sarkar, S., Ravikumar, B., Floto, R. A., & Rubinsztein, D. C. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2008.110 · Cited by 578 · see citing works
Colacurcio, D. J., & Nixon, R. A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.004 · Cited by 548 · see citing works
“…Reviews 32 (2016) 75–88 83 Vicente et al., 2008) and oxidative stress (Kiffin et al., 2006; Porter et al., 2013) in conjunction with -syn (Cuervo et al., 2004) may negatively affect lysosomal function, further study on the susceptibilities of dopaminergic neurons to…”
BackgroundLRRK2 activation in idiopathic Parkinson’s disease
Maio, R. D., Hoffman, E. K., Rocha, E. M., Keeney, M. T., Sanders, L. H., Miranda, B. R. D., Zharikov, A., Laar, A. D. V., Stepan, A. F., Lanz, T. A., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aar5429 · Cited by 571 · see citing works
“Both chaperone-mediated autophagy (CMA) and macroautophagy play roles in -synuclein degradation (27, 28).”
Glucocerebrosidase Deficiency in Substantia Nigra of Parkinson Disease Brains
Gegg, M. E., Burke, D., Heales, S., Cooper, J., Hardy, J., Wood, N., & Schapira, A. (2012) · Annals of Neurology · doi:10.1002/ana.23614 · Cited by 551 · see citing works
Chaperone-mediated autophagy markers in Parkinson disease brains.
Álvarez-Erviti, L., Rodríguez-Oroz, M., Cooper, J., Caballero, C., Ferrer, I., Obeso, J., & Schapira, A. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.198 · Cited by 525 · see citing works
Lithium delays progression of amyotrophic lateral sclerosis
Fornai, F., Longone, P., Cafaro, L., Kastsiuchenka, O., Ferrucci, M., Manca, M. L., Lazzeri, G., Spalloni, A., Bellio, N., Lenzi, P., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708022105 · Cited by 550 · see citing works
Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration
Choi, I., Zhang, Y., Seegobin, S. P., Pruvost, M., Wang, Q., Purtell, K., Zhang, B., & Yue, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-15119-w · Cited by 549 · see citing works
The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease
Pan, T., Kondo, S., Le, W., & Jankovic, J. J. (2008) · Brain · doi:10.1093/brain/awm318 · Cited by 546 · see citing works
“Furthermore, it has been shown that wild-type -synuclein, but not the mutant -synuclein, is selectively translocated into lysosomes for degradation by the CMA pathway (Cuervo et al., 2004).”
BackgroundInfluentialMicroglial exosomes facilitate α-synuclein transmission in Parkinson’s disease
Guo, M., Wang, J., Zhao, Y., Feng, Y., Han, S., Dong, Q., Cui, M., & Tieu, K. (2020) · Brain · doi:10.1093/brain/awaa090 · Cited by 522 · see citing works
“Autophagy is a vital pathway by which a-syn is degraded (Webb et al., 2003; Cuervo et al., 2004; Lee et al., 2004).”
BackgroundDehay, B., Bourdenx, M., Gorry, P., Przedborski, S., Vila, M., Hunot, S., Singleton, A., Olanow, C. W., Merchant, K., Bézard, E., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00006-x · Cited by 530 · see citing works
Maiti, P., Manna, J., & Dunbar, G. L. (2017) · Translational Neurodegeneration · doi:10.1186/s40035-017-0099-z · Cited by 534 · see citing works
Murrow, L. M., & Debnath, J. (2012) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-163918 · Cited by 526 · see citing works
Lin, X. Z., Parisiadou, L., Gu, X., Wang, L., Shim, H., Sun, L., Xie, C., Long, C.-X., Yang, W.-J., Ding, J., et al. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.006 · Cited by 513 · see citing works
Autophagy in health and disease: A comprehensive review
Saha, S., Panigrahi, D. P., Patil, S., & Bhutia, S. K. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.05.007 · Cited by 514 · see citing works
α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis
Mehra, S., Sahay, S., & Maji, S. K. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.03.001 · Cited by 507 · see citing works
Protective and toxic roles of dopamine in Parkinson's disease
Segura‐Aguilar, J., Paris, I. B., Muñoz, P., Ferrari, E., Zecca, L., & Zucca, F. A. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12686 · Cited by 499 · see citing works
“Finally, the formation of adducts of aminochrome with alpha synuclein inhibit chaperon-mediated autophagy (Cuervo et al. 2004); (iv) aminochrome induces oxidative stress when flavoenzymes catalyze its one-electron reduction to leucoaminochrome o-semiquinone radical (Fig.”
BackgroundAggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy
Lamark, T., & Johansen, T. (2012) · International Journal of Cell Biology · doi:10.1155/2012/736905 · Cited by 490 · see citing works
“In PD and certain tauopathies, there is a block in CMA because accumulation of α-synuclein or toxic forms of tau inhibit the CMA translocation complex [207, 210, 211].”
BackgroundReduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease
Murphy, K. E., Gysbers, A. M., Abbott, S. K., Tayebi, N., Kim, W. S., Sidransky, E., Cooper, A., Garner, B., & Halliday, G. M. (2014) · Brain · doi:10.1093/brain/awt367 · Cited by 475 · see citing works
Resveratrol-Activated AMPK/SIRT1/Autophagy in Cellular Models of Parkinson’s Disease
Wu, Y., Li, X., Zhu, J. X., Xie, W., Le, W., Fan, Z., Jankovic, J. J., & Pan, T. (2011) · Neurosignals · doi:10.1159/000328516 · Cited by 492 · see citing works
Zhang, C., & Cuervo, A. M. (2008) · Nature Medicine · doi:10.1038/nm.1851 · Cited by 520 · see citing works
Self-citationThe different autophagy degradation pathways and neurodegeneration
Fleming, A., Bourdenx, M., Fujimaki, M., Karabiyik, C., Krause, G. J., Lopez, A., Martín‐Segura, A., Puri, C., Scrivo, A., Skidmore, J., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.017 · Cited by 485 · see citing works
Self-citationEffects of α-Synuclein Immunization in a Mouse Model of Parkinson’s Disease
Masliah, E., Rockenstein, E., Adame, A., Alford, M., Crews, L., Hashimoto, M., Seubert, P., Lee, M., Goldstein, J., Chilcote, T., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.05.010 · Cited by 542 · see citing works
Consequences of the selective blockage of chaperone-mediated autophagy
Massey, A. C., Kaushik, S., Sovak, G., Kiffin, R., & Cuervo, A. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507436103 · Cited by 529 · see citing works
Self-citationMechanisms of Parkinson's Disease Linked to Pathological α-Synuclein: New Targets for Drug Discovery
Lee, V. M. ‐., & Trojanowski, J. Q. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.026 · Cited by 478 · see citing works
Protein Homeostasis and Aging: the importance of exquisite quality control
Koga, H., Kaushik, S., & Cuervo, A. M. (2011) · Ageing research reviews · doi:10.1016/j.arr.2010.02.001 · Cited by 476 · see citing works
Self-citationShults, C. W. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509567103 · Cited by 476 · see citing works
Autophagy and neurodegeneration: when the cleaning crew goes on strike
Martínez‐Vicente, M., & Cuervo, A. M. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70076-5 · Cited by 472 · see citing works
Self-citationThe emerging mechanisms and functions of microautophagy
Wang, L., Klionsky, D. J., & Shen, H. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00529-z · Cited by 473 · see citing works
The Role of Autophagy in Parkinson's DiseasePreprint
Lynch-Day, M. A., Mao, K., Wang, K., Zhao, M., & Klionsky, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009357 · Cited by 459 · see citing works
“a-Synuclein in its native form is degraded by chaperone-mediated autophagy (Cuervo et al. 2004).”
BackgroundDynein mutations impair autophagic clearance of aggregate-prone proteins
Ravikumar, B., Acevedo‐Arozena, A., Imarisio, S., Berger, Z., Vacher, C., O’Kane, C. J., Brown, S. D. M., & Rubinsztein, D. C. (2005) · Nature Genetics · doi:10.1038/ng1591 · Cited by 458 · see citing works
“Furthermore, A53T mutant α-synuclein is cleared by autophagy but not by chaperone-mediated autophag”
BackgroundChinta, S. J., Mallajosyula, J. K., Rane, A., & Andersen, J. K. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.09.061 · Cited by 451 · see citing works
“α-Syn has been reported to undergo degradation by the proteasome and by alternative pathways such as autophagy [7].”
Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates
Collier, T. J., Kanaan, N. M., & Kordower, J. H. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3039 · Cited by 453 · see citing works
“The ubiquitylation of α-synuclein within Lewy bodies suggests a connection with the proteasome, and α-synuclein is a known substrate of chaperone-mediated autophagy involving the lysosom”
BackgroundControl of autophagy as a therapy for neurodegenerative disease
Harris, H., & Rubinsztein, D. C. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.200 · Cited by 445 · see citing works
- Authors
- Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D.
- Affiliations
- Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
- Brigham and Women's Hospital (US)
- Venue
- Science
- Published
- 2004-08-27
- Volume
- 305
- Issue
- 5688
- Pages
- 1292-1295
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2068288454
- Cited by
- 2,024
- References
- 28
- Citations by year
- 2026: 64 · 2025: 77 · 2024: 102 · 2023: 71 · 2022: 107 · 2021: 114 · 2020: 128 · 2019: 114 · 2018: 117 · 2017: 101 · 2016: 95 · 2015: 92 · 2014: 93 · 2013: 108 · 2012: 119
- FWCI
- 34.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-021904)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, chaperone-mediated autophagy, Parkinson's disease, lysosomal degradation, A53T mutant, Lewy bodies, gain-of-function toxicity, protein degradation pathways
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Glyceraldehyde-3-Phosphate Dehydrogenases, Half-Life, Intracellular Membranes, Lysosomes, Male, Mutation, Nerve Tissue Proteins, Neurons, Protein Binding, Antigens, CD, PC12 Cells, Rats, Wistar, Molecular Chaperones, Amino Acid Motifs, Protein Transport, Mice, Rats, Synucleins, alpha-Synuclein, Lysosomal Membrane Proteins
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