The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index.
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 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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
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Cites
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469
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 4,296
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
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
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
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 828
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
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 685
Self-citationStefanis, L., Larsen, K. E., Rideout, H. J., Sulzer, D., & Greene, L. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-24-09549.2001 · Cited by 584
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
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Chaperone-Mediated Autophagy Is Required for Tumor Growth
Kon, M., Kiffin, R., Koga, H., Chapochnick, J., Macián, F., Varticovski, L., & Cuervo, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3003182 · Cited by 269
Self-citationAutophagy and A lpha‐ S ynuclein: R elevance to P arkinson's D isease and R elated S ynucleopathies
Xilouri, M., Brekk, O. R., & Stefanis, L. (2016) · Movement Disorders · doi:10.1002/mds.26477 · Cited by 280
Self-citationChaperone-mediated autophagy: selectivity pays off
Cuervo, A. M. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.10.003 · Cited by 260
Self-citationBraak, H., & Del Tredici, K. (2017) · Journal of Parkinson’s Disease · doi:10.3233/jpd-179001 · Cited by 372
Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders
Cai, Y. C., Arikkath, J., Yang, L., Guo, M., Periyasamy, P., & Buch, S. J. (2016) · Autophagy · doi:10.1080/15548627.2015.1121360 · Cited by 259
“(95VKKDQ99), and its degradation can be blocked by the lysosomal proteolysis inhibitor ammonium chloride.(139) PARK2”
BackgroundProtein damage, repair and proteolysis
Chondrogianni, N., Petropoulos, I., Grimm, S., Georgila, K., Catalgol, B., Friguet, B., Grune, T., & Gonos, E. S. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.09.001 · Cited by 271
Cappai, R., Leck, S., Tew, D. J., Williamson, N. A., Smith, D. P., Galatis, D., Sharpies, R. A., Curtain, C. C., Ali, F. E. A., Cherny, R. A., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-3437fje · Cited by 254
“Mutant α-SN, however, is unable to be properly processed by the proteasome ( 4 ).”
BackgroundProteome-wide analysis of chaperone-mediated autophagy targeting motifs
Kirchner, P., Bourdenx, M., Madrigal-Matute, J., Tiano, S., Diaz, A., Bartholdy, B. A., Will, B., & Cuervo, A. M. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000301 · Cited by 257
Self-citationRole of DJ-1 in the mechanism of pathogenesis of Parkinson's disease
Dolgacheva, L. P., Berezhnov, A. V., Fedotova, E. I., Zinchenko, V. P., & Abramov, A. Y. (2019) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-019-09798-4 · Cited by 254
“Wild-type α -Syn is a substrate of CMA and CMA dysfunction may contribute an increase in pathological α -synuclein aggregates (Vogiatzi et al. 2008; Cuervo et al. 2004).”
BackgroundProtein degradation pathways in Parkinson’s disease: curse or blessing
Ebrahimi‐Fakhari, D., Wahlster, L., & McLean, P. J. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1004-6 · Cited by 261
“Rat α-synuclein, containing the A53T substitution just like familial cases of PD [80], seems to be degraded by the ALP, macroautophagy [162] and CMA [33,162], although ambiguous findings concerning the latter exist [33].”
BackgroundInfluentialGenetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease
Gan-Or, Z., Dion, P. A., & Rouleau, G. A. (2015) · Autophagy · doi:10.1080/15548627.2015.1067364 · Cited by 260
Hsp70 – a master regulator in protein degradation
Fernández-Fernández, M. R., Gragera, M., Ochoa‐Ibarrola, L., Quintana‐Gallardo, L., & Valpuesta, J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12751 · Cited by 260
Mitochondria-associated membranes in aging and senescence: structure, function, and dynamics
Janikiewicz, J., Szymański, J., Malińska, D., Patalas‐Krawczyk, P., Michalska, B., Duszyński, J., Giorgi, C., Bonora, M., Dobrzyń, A., & Wieckowski, M. R. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0105-5 · Cited by 256
Bassil, F., Brown, H. J., Pattabhiraman, S., Iwasyk, J. E., Maghames, C. M., Meymand, E. S., Cox, T. O., Riddle, D. M., Zhang, B., Trojanowski, J. Q., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.10.010 · Cited by 246
“Since prior studies showed that the autophagy-lysosome pathway mediates intraneuronal clearance of accumulated α-syn (Cuervo et al., 2004), we explored defective protein clearance as a possible explanation for increased pathological α-syn in α-syn mpff-injected 5xFAD compared with α-syn mpff-injected WT mice.”
Autophagy, aging, and age-related neurodegeneration
Palmer, J. E., Wilson, N., Son, S. M., Obrocki, P., Wróbel, L., Rob, M., Takla, M., Korolchuk, V. I., & Rubinsztein, D. C. (2024) · Neuron · doi:10.1016/j.neuron.2024.09.015 · Cited by 277
“113 Furthermore, A53T, but not wild-type, a -Syn alters mitophagy clearance.”
BackgroundRole of metabolism in neurodegenerative disorders
Procaccini, C., Santopaolo, M., Faicchia, D., Colamatteo, A., Formisano, L., de Candia, P., Galgani, M., De Rosa, V., & Matarese, G. (2016) · Metabolism · doi:10.1016/j.metabol.2016.05.018 · Cited by 258
Benskey, M. J., Perez, R. G., & Manfredsson, F. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13570 · Cited by 257
“Accordingly, the subsequent accumulation of a-syn, as well as other damaged or potentially toxic proteins, has been proposed as a possible gain of function mechanism underlying the toxicity of these a-syn mutants (Cuervo et al. 2004).”
BackgroundMartínez‐Vicente, M., Sovak, G., & Cuervo, A. M. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.07.005 · Cited by 249
Self-citationPathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease
Overk, C. R., & Masliah, E. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.015 · Cited by 242
Nix directly binds to GABARAP: A possible crosstalk between apoptosis and autophagy
Schwarten, M., Mohrlüder, J., Ma, P., Stoldt, M., Thielmann, Y., Stangler, T., Hersch, N., Hoffmann, B., Merkel, R., & Willbold, D. (2009) · Autophagy · doi:10.4161/auto.5.5.8494 · Cited by 224
Autophagy in Innate and Adaptive Immunity
Xu, Y., & Eissa, N. T. (2010) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200909-103js · Cited by 243
The Role of α-Synuclein Oligomers in Parkinson’s Disease
Du, X.-Y., Xie, X.-X., & Liu, R.-T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228645 · Cited by 234
“These mutations inhibit the degradation of α-syn, resulting in α-syn accumulation [6].”
BackgroundAutophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases
Djajadikerta, A., Keshri, S., Tanasa, M. P., Prestil, R., Ryan, L., & Rubinsztein, D. C. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.035 · Cited by 244
“[94] Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D.”
BackgroundEjlerskov, P., Rasmussen, I., Nielsen, T. T., Bergström, A., Tohyama, Y., Jensen, P. H., & Vilhardt, F. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.401174 · Cited by 242
Interplay of pathogenic forms of human tau with different autophagic pathways
Caballero, B., Wang, Y., Diaz, A., Tasset, I., Juste, Y. R., Stiller, B., Mandelkow, E., Mandelkow, E., & Cuervo, A. M. (2018) · Aging Cell · doi:10.1111/acel.12692 · Cited by 213
“Studies from our laboratories and others, with pathogenic proteins such as alpha-synuclein, support that the mechanism of their toxic effect on autophagy is the same independent of the cell type (Cuervo et al., 2004).”
BackgroundResultSelf-citationFirefly luciferase mutants as sensors of proteome stress
Gupta, R., Kasturi, P., Bracher, A., Loew, C., Zheng, M., Villella, A., Garza, D., Hartl, F. U., & Raychaudhuri, S. (2011) · Nature Methods · doi:10.1038/nmeth.1697 · Cited by 219
Song, Q., Meng, B., Xu, H., & Mao, Z. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00196-0 · Cited by 244
Parkinson's Disease Genetics and Pathophysiology
Vázquez-Vélez, G. E., & Zoghbi, H. Y. (2021) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-100720-034518 · Cited by 244
Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease
George, S., Rey, N. L., Tyson, T., Esquibel, C., Meyerdirk, L., Schulz, E., Pierce, S., Burmeister, A. R., Madaj, Z., Steiner, J. A., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0335-3 · Cited by 229
Glucocerebrosidase mutations are an important risk factor for Lewy body disorders
Göker-Alpan, Ö., Giasson, B. I., Eblan, M. J., Nguyen, J., Hurtig, H. I., Lee, V. M.-Y., Trojanowski, J. Q., & Sidransky, E. (2006) · Neurology · doi:10.1212/01.wnl.0000230215.41296.18 · Cited by 230
Chiu, C., & Chuang, D. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.07.006 · Cited by 232
Inhibitory effect of dietary lipids on chaperone-mediated autophagy
Rodríguez‐Navarro, J. A., Kaushik, S., Koga, H., Dall’Armi, C., Shui, G., Wenk, M. R., Paolo, G. D., & Cuervo, A. M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113036109 · Cited by 233
Self-citationKabuta, T., Furuta, A., Aoki, S., Furuta, K., & Wada, K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801918200 · Cited by 227
Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain
Eslamboli, A., Romero‐Ramos, M., Bürger, C., Björklund, T., Muzyczka, N., Mandel, R. J., Baker, H. F., Ridley, R. M., & Kirik, D. (2007) · Brain · doi:10.1093/brain/awl382 · Cited by 233
“It has recently been shown that wt- -syn could be degraded by the lysosomal pathway, while the A53T mutation impairs the lysosomal uptake leading to decrease protein degradation (Cuervo et al., 2004).”
BackgroundChemical modulation of chaperone-mediated autophagy by retinoic acid derivatives
Anguiano, J., Garner, T. P., Mahalingam, M., Das, B. C., Gavathiotis, E., & Cuervo, A. M. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1230 · Cited by 232
Self-citationShared dysregulated pathways lead to Parkinson's disease and diabetes
Santiago, J. A., & Potashkin, J. A. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.01.002 · Cited by 232
Targeting lysosomes in human disease: from basic research to clinical applications
Cao, M., Luo, X., Wu, K., & He, X. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00778-y · Cited by 225
Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies
Villar‐Piqué, A., da Fonseca, T. L., & Outeiro, T. F. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13249 · Cited by 243
“This inhibition, caused by the binding of a-syn to LAMP2, a specific receptor on the lysosome, might favour asyn accumulation and disturb the entire cellular homeostasis (Cuervo et al. 2004).”
BackgroundAutophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy
Tan, C., Yu, J., Tan, M., Jiang, T., Zhu, X., & Tan, L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.019 · Cited by 224
“CMA, a type of selective autophagy, was different from other types of autophagy because of the unique way in which its substrate proteins are targeted one-by-one to the surface of the lysosomes, and then enter the digestive organelles (Cuervo et al., 2004).”
Mitophagy and Parkinson's disease: The PINK1–parkin link
Deas, E., Wood, N. W., & Plun‐Favreau, H. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.08.007 · Cited by 230
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
Caballero, B., Bourdenx, M., Luengo, E., Diaz, A., Sohn, P. D., Chen, X., Wang, C., Juste, Y. R., Wegmann, S., Patel, B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22501-9 · Cited by 223
Self-citationParkinson’s disease as a result of aging
Rodriguez, M., Rodriguez‐Sabate, C., Morales, I., Sanchez, A., & Sabate, M. (2015) · Aging Cell · doi:10.1111/acel.12312 · Cited by 214
“…and John Wiley & Sons Ltd. disorders where this could explain the accumulation of proteins in cytosolic aggregates (e.g. of a-synuclein in Lewy bodies of PD) (Stefanis et al., 2001; Webb et al., 2003; Cuervo et al., 2004; Martinez-Vicente et al., 2008; Wong & Cuervo, 2010; Friedman et al., 2012).”
BackgroundNeurotoxicity of methamphetamine: Main effects and mechanisms
Jayanthi, S., Daiwile, A. P., & Cadet, J. L. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113795 · Cited by 238
Cell-produced α-synuclein oligomers are targeted to, and impair, the 26S proteasome
Emmanouilidou, E., Stefanis, L., & Vekrellis, K. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.07.008 · Cited by 236
Self-citationHypoxia increases Aβ generation by altering β- and γ-cleavage of APP
Li, L., Zhang, X., Yang, D., Luo, G., Chen, S., & Le, W. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.10.011 · Cited by 220
Follett, J., Norwood, S. J., Hamilton, N., Mohan, M., Kovtun, O., Tay, S. V., Yang, Z., Wood, S. A., Mellick, G. D., Silburn, P. A., et al. (2013) · Traffic · doi:10.1111/tra.12136 · Cited by 223
“of α-synuclein to lysosomal membranes leading to inhibition of lysosome function (8), (ii) cathepsin D, a lysosomal protease and cation-independent mannose-6-phosphate receptor (CI-M6PR) ligand, is able to degrade α-synuclein in vivo and in vitro (9,10) and (iii) the cathepsin D knockout mouse model shows marked incre…”
BackgroundAutophagy and mitophagy in cellular damage control
Zhang, J. (2013) · Redox Biology · doi:10.1016/j.redox.2012.11.008 · Cited by 228
“However, a-synuclein that is phosphorylated at serine 129 as appears in Lewy Bodies in Parkinson’s disease, and a-synuclein that is mutated in familial Parkinson’s disease cannot be degraded by chaperone-mediated autophagy [10], and is thus presumably highly sensitive to blockade of macroautophagy.”
BackgroundKabuta, T., Suzuki, Y., & Wada, K. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603337200 · Cited by 220
Glucocerebrosidase and Parkinson disease: Recent advances
Schapira, A. H. V. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.03.013 · Cited by 228
“SNCA is predominantlymetabolised through chaperonemediated autophagy (CMA) and abnormalities of CMA have been identified in PD brain (Alvarez-Erviti Please cite this article as: Schapira, A.H.V., Glucocerebrosidase and Park dx.doi.org/10.1016/j.mcn.2015.03.013 et al., 2010; Cuervo et al., 2004).”
InfluentialMechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
Chu, C. T. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.015 · Cited by 218
Cdk5: a multifaceted kinase in neurodegenerative diseases
Cheung, Z. H., & Ip, N. Y. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.11.003 · Cited by 233
Equine Pituitary Pars Intermedia Dysfunction
McFarlane, D. (2011) · Veterinary Clinics of North America Equine Practice · doi:10.1016/j.cveq.2010.12.007 · Cited by 228
Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease
Ko, D. C., Milenković, L., Beier, S., Manuel, H., Buchanan, J., & Scott, M. P. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010007 · Cited by 220
“]. The role of autophagy in neurodegenerative disease extends to Huntington disease and Parkinson disease [”
BackgroundRapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation
Fan, X., Wu, J., Lu, J., Wang, J., & Wang, Y. T. (2014) · Nature Neuroscience · doi:10.1038/nn.3637 · Cited by 222
“As α -synuclein harbors an endogenous CMA targeting motif ( 95 VKKDQ 99 22), TAT-β synCTM could be enhancing its accessibility or functioning in an additive manner.”
InfluentialDopamine Oxidation and Autophagy
Muñoz, P., Huenchuguala, S., Paris, I., & Segura-Aguilar, J. (2012) · Parkinson's Disease · doi:10.1155/2012/920953 · Cited by 214
“Interestingly, the pathogenic A53T and A30P α-synuclein mutants inhibit their own degradation and that of other substrates [64].”
BackgroundA photoconvertible fluorescent reporter to track chaperone-mediated autophagy
Koga, H., Martínez‐Vicente, M., Macián, F., Verkhusha, V. V., & Cuervo, A. M. (2011) · Nature Communications · doi:10.1038/ncomms1393 · Cited by 226
Self-citationSeeking a Mechanism for the Toxicity of Oligomeric α-Synuclein
Hall‐Roberts, H., & Brown, D. R. (2015) · Biomolecules · doi:10.3390/biom5020282 · Cited by 222
“Non-aggregated -synuclein, particularly with A30P or A53T mutations, has the ability to impair the LAMP2A-mediated uptake of CMA substrates into lysosomes [96,97].”
BackgroundUbiquitin–proteasome system and Parkinson's disease
Olanow, C. W., & McNaught, K. S. P. (2006) · Movement Disorders · doi:10.1002/mds.21013 · Cited by 219
Advancement in the modelling and therapeutics of Parkinson’s disease
Nand, S., & Singh, P. (2020) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2020.101752 · Cited by 214
The role of free radicals in the aging brain and Parkinson’s Disease: Convergence and parallelism
Kumar, H., Lim, H.-W., More, S. V., Kim, B.-W., Koppula, S., Kim, I. S., & Choi, D.-K. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms130810478 · Cited by 212
“The ubiquitylation of α-synuclein within LBs suggests a connection with proteasomes, and α-synuclein is a known substrate of chaperone-mediated autophagy involving lysosomes [114–116].”
BackgroundAutophagy in innate and adaptive immunity
Deretic, V. P. (2005) · Trends in Immunology · doi:10.1016/j.it.2005.08.003 · Cited by 218
Chaperone-mediated autophagy at a glance
Kaushik, S., Bandyopadhyay, U., Sridhar, S., Kiffin, R., Martínez‐Vicente, M., Kon, M., Orenstein, S. J., Wong, E. S. P., & Cuervo, A. M. (2011) · Journal of Cell Science · doi:10.1242/jcs.073874 · Cited by 219
“For example, a-synuclein (Cuervo et al., 2004; Martinez-Vicente et al., 2008; Xilouri et al., 2009; Mak et al., 2010) and UCHL1 (Kabuta et al., 2008), proteins associated with Parkinson’s disease pathogenesis, bind with abnormally high affinity to LAMP-2A at the lysosomal membrane.”
BackgroundSelf-citationCausative Links between Protein Aggregation and Oxidative Stress: A Review
Lévy, E., Banna, N. E., Baïlle, D., Heneman-Masurel, A., Truchet, S., Rezaei, H., Huang, M., Béringue, V., Martin, D., & Vernis, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163896 · Cited by 210
Renna, M., Jiménez-Sánchez, M., Sarkar, S., & Rubinsztein, D. C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.r109.072181 · Cited by 215
Modelling the molecular mechanisms of aging
Auley, M. T. M., Guimera, A. M., Hodgson, D., Mcdonald, N., Mooney, K. M., Morgan, A. E., & Proctor, C. J. (2017) · Bioscience Reports · doi:10.1042/bsr20160177 · Cited by 214
Autophagy as an immune defense mechanism
Deretic, V. P. (2006) · Current Opinion in Immunology · doi:10.1016/j.coi.2006.05.019 · Cited by 208
Microglia as modulators of exosomal alpha-synuclein transmission
Xia, Y. F., Zhang, G., Han, C., Ma, K., Guo, X., Wan, F. J., Kou, L., Yin, S., Liu, L., Huang, J., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1404-9 · Cited by 212
Ho, P. W., Leung, C.-T., Liu, H., Pang, S. Y.-Y., Lam, C. S.-C., Xian, J., Li, L., Kung, M. H.-W., Ramsden, D. B., & Ho, S. (2019) · Autophagy · doi:10.1080/15548627.2019.1603545 · Cited by 215
Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration
Xilouri, M., Brekk, O. R., Landeck, N., Pitychoutis, P. M., Papasilekas, T., Papadopoulou-Daifoti, Z., Kirik, D., & Stefanis, L. (2013) · Brain · doi:10.1093/brain/awt131 · Cited by 215
“The Parkinson’s disease-linked mutants A53T and A30P cannot be degraded through CMA, but instead bind strongly to the CMA receptor, lysosomal-associated membrane protein 2a (Lamp2a) and impair CMA (Cuervo et al., 2004; Xilouri et al., 2009).”
BackgroundResultInfluentialSelf-citationCellular Proteostasis in Neurodegeneration
Kurtishi, A., Rosen, B., Patil, K. S., Alves, G. W., & Møller, S. G. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1334-z · Cited by 210
Vidović, M., & Rikalović, M. (2022) · Cells · doi:10.3390/cells11111732 · Cited by 214
Prediction of "hot spots" of aggregation in disease-linked polypeptides
de Groot, N. S., Pallarès, I., Avilés, F. X., Vendrell, J., & Ventura, S. (2005) · BMC Structural Biology · doi:10.1186/1472-6807-5-18 · Cited by 211
“In fact the effects of α-synuclein mutations have been associated either to an impaired degradation inside lysosomes or to a reduced axonal transport of the variants [ 43 ,44].”
Alvarez‐Erviti, L., Seow, Y., Schapira, A. H. V., Rodríguez-Oroz, M. C., Obeso, J. A., & Cooper, J. A. D. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.73 · Cited by 208
Conformational Equilibria in Monomeric α-Synuclein at the Single-Molecule Level
Sandal, M., Valle, F., Tessari, I., Mammi, S., Bergantino, E., Musiani, F., Brucale, M., Bubacco, L., & Samorì, B. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060006 · Cited by 209
“] and impaired degradation by chaperone-mediated autophagy [”
BackgroundAutophagy and Its Normal and Pathogenic States in the Brain
Yamamoto, A., & Yue, Z. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014149 · Cited by 204
“Both wildtype α-syn and LRRK2 proteins are CMA substrates, and their PD-linked mutations impair CMA-mediated degradation (Cuervo et al. 2004, Orenstein et al. 2013).”
BackgroundMechanisms of Suppression of α-Synuclein Neurotoxicity by Geldanamycin in Drosophila
Auluck, P. K., Meulener, M. C., & Bonini, N. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412106200 · Cited by 207
Molecular and clinical prodrome of Parkinson disease: implications for treatment
Schapira, A. H. V., & TOLOSA, E. S. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.52 · Cited by 210
Functional cooperation of α-synuclein and VAMP2 in synaptic vesicle recycling
Sun, J., Wang, L., Bao, H., Premi, S., Das, U., Chapman, E. R., & Roy, S. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903049116 · Cited by 202
Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein
Lee, H.-J., Cho, E.-D., Lee, K., Kim, J., Cho, S., & Lee, S. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.45 · Cited by 204
The Autophagy Lysosomal Pathway and Neurodegeneration
Finkbeiner, S. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033993 · Cited by 196
“Interestingly, the KFERQ motif is found in ∼30% of the proteome and in many proteins implicated in neurodegenerative diseases including α-synuclein (Olson et al. 1991; Cuervo et al. 2004; Martinez-Vicente et al. 2008).”
BackgroundGenome-Wide Screen for Modifiers of Ataxin-3 Neurodegeneration in Drosophila
Bilen, J., & Bonini, N. M. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030177 · Cited by 199
“inhibition of normal activity would contribute to disease pathology [47–49].”
BackgroundMiura, E., Hasegawa, T., Konno, M., Suzuki, M., Sugeno, N., Fujikake, N., Geisler, S., Tabuchi, M., Oshima, R., Kikuchi, A., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.07.014 · Cited by 204
“…the amino acid sequence of αSYN contains a pentapeptide succession consistent with a CMA recognition motif and in vitro experiments demonstrated that this motif is essential for the internalization of αSYN into the lysosomal lumen and for degradation by lysosomal proteases (Cuervo et al., 2004).”
Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications
Banerjee, R., Beal, M. F., & Thomas, B. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.09.001 · Cited by 199
Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress
Höhn, A., Tramutola, A., & Cascella, R. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5497046 · Cited by 208
Bejarano, E., & Cuervo, A. M. (2010) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200909-102js · Cited by 200
Self-citationCellular and Molecular Basis of Neurodegeneration in Parkinson Disease
Zeng, X., Geng, W.-S., Jia, J., Chen, L., & Zhang, P.-P. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00109 · Cited by 203
Ferrer, I., Martinez, A., Blanco, R. E., Dalfó, E., & Carmona, M. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0482-8 · Cited by 191
“The role of autophagy, including CMA and macroautophagy in PD, is postulated mainly on the basis of observations in cell models (Stefanis et al. 2001; Cuervo et al. 2004; Engelender 2008; Martı́nez-Vicente et al. 2008; Xilouri et al. 2008, Vogiatzi et al. 2008; Mak et al. 2010).”
BackgroundGenetics of Parkinsonʼs disease
Gasser, T. (2005) · Current Opinion in Neurology · doi:10.1097/01.wco.0000170951.08924.3d · Cited by 192
Loss of hepatic chaperone‐mediated autophagy accelerates proteostasis failure in aging
Schneider, J. L., Villarroya, J., Díaz-Carretero, A. M., Patel, B., Urbanska, A. M., Thi, M. M., Villarroya, F., Santambrogio, L., & Cuervo, A. M. (2015) · Aging Cell · doi:10.1111/acel.12310 · Cited by 201
Self-citationda Silveira, S. A., Schneider, B. L., Cifuentes-Díaz, C., Sage, D., Abbas‐Terki, T., Iwatsubo, T., Unser, M. A., & Aebischer, P. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn417 · Cited by 196
“Reciprocally, the expression of mutant a-syn in rat ventral midbrain cultures blocks lysosomal function ( 51 ).”
BackgroundMutant LRRK2 Elicits Calcium Imbalance and Depletion of Dendritic Mitochondria in Neurons
Cherra, S. J., Steer, E. K., Gusdon, A. M., Kiselyov, K. I., & Chu, C. T. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.10.027 · Cited by 190
Bourdenx, M., Koulakiotis, N. S., Sanoudou, D., Bézard, E., Dehay, B., & Tsarbopoulos, A. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.07.003 · Cited by 202
“Of interest, disease-related mutations such as p.A30P or p.A53T have been shown to specifically inhibit one component of the ALP: chaperone-mediated autophagy (CMA) (Cuervo et al., 2004).”
BackgroundInfluentialLin, X. Z., Parisiadou, L., Sgobio, C., Liu, G., Yu, J. H., Sun, L., Shim, H., Gu, X., Luo, J., Long, C., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1731-12.2012 · Cited by 192
“Our observations of the alterations of P62, LC3, and LAMP2 expression in the mDA neurons of A53T mice confirm the previous studies about the involvement of -syn in the autophagy/lysosome-dependent degradation pathways (Cuervo et al., 2004).”
BackgroundInfluentialKaminskyy, V. O., & Zhivotovsky, B. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.05.013 · Cited by 193
The role of Ca2+ signaling in Parkinson's disease
Zaichick, S., McGrath, K. M., & Caraveo, G. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.028738 · Cited by 191
“Lysosomes and autosomes are especially important for the degradation of proteasome-insensitive protein aggregates, like those generated by α-synuclein; such degradation is dependent on lysosomal Ca2+ (Cuervo et al., 2004; Klionsky et al., 2010; Luzio et al., 2007, 2000).”
BackgroundFamilial Mutants of α-Synuclein with Increased Neurotoxicity Have a Destabilized Conformation
Bertoncini, C. W., Fernández, C. O., Griesinger, C., Jovin, T. M., & Zweckstetter, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500288200 · Cited by 191
Autophagy in disease: a double-edged sword with therapeutic potential
Martinet, W., Agostinis, P., Vanhoecke, B., Dewaele, M., & de Meyer, G. R. Y. (2009) · Clinical Science · doi:10.1042/cs20080508 · Cited by 186
Discovery of a novel type of autophagy targeting RNA
Fujiwara, Y., Furuta, A., Kikuchi, H., Aizawa, S., Hatanaka, Y., Konya, C., Uchida, K., Yoshimura, A., Tamai, Y., Wada, K., et al. (2013) · Autophagy · doi:10.4161/auto.23002 · Cited by 197
Autophagic and endo-lysosomal dysfunction in neurodegenerative disease
Malik, B. R., Maddison, D. C., Smith, G. A., & Peters, O. M. (2019) · Molecular Brain · doi:10.1186/s13041-019-0504-x · Cited by 187
LRRK2 at the interface of autophagosomes, endosomes and lysosomes
Roosen, D. A., & Cookson, M. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0140-1 · Cited by 186
“The majority of α-synuclein is degraded through the lysosome, perhaps by a specialized process called chaperone-mediated autophagy (CMA) [29].”
Influential
Metadata
- 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 › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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