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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In the citing paper
“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]
Citations
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
Cited by
Sorted by citations
Items 1,001–1,006 of 1,006
Lysosomal Functions in Glia Associated with Neurodegeneration
Kreher, C., Favret, J., Maulik, M., & Shin, D. (2021) · Biomolecules · doi:10.3390/biom11030400 · Cited by 38
“Autophagic dysfunction has been shown to contribute to delays in remyelination after acute and chronic demyelinating insults [29,111,137,138].”
BackgroundKakoty, V., K C, S., Dubey, S. K., Yang, C.-H., & Taliyan, R. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00144 · Cited by 33
Doublecortin-like Kinase 1 Regulates α-Synuclein Levels and Toxicity
Vázquez-Vélez, G. E., Gonzales, K. A., Revelli, J.-P., Adamski, C. J., Alavi Naini, F., Bajić, A., Craigen, E., Richman, R., Heman-Ackah, S. M., Wood, M. J. A., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.1076-19.2019 · Cited by 22
“This is consistent with reports indicating that the primary mode of -Syn degradation is lysosomal (Cuervo et al., 2004; Lee et al., 2004; Vogiatzi et al., 2008; Tofaris et al., 2011; Oueslati et al., 2013).”
ResultManecka, D.-L., Vanderperre, B., Fon, E. A., & Durcan, T. M. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00311 · Cited by 21
“This impairs CMA-mediated degradation of these proteins and CMA activity, contributing to PD pathology (Cuervo et al., 2004; Orenstein et al., 2013).”
BackgroundLane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3
Khan, M. R., Yin, X., Kang, S.-U., Mitra, J., Wang, H., Brahmachari, S., Karuppagounder, S. S., Kimura, Y., Jhaldiyal, A., Kim, H. H., et al. (2022) · doi:10.1101/2022.10.03.510455
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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