The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells
Open accessAbstract
Alpha-synuclein (ASYN) is crucial in Parkinson disease (PD) pathogenesis. Increased levels of wild type (WT) ASYN expression are sufficient to cause PD in humans. The manner of post-transcriptional regulation of ASYN levels is controversial. Previously, we had shown that WT ASYN can be degraded by chaperone-mediated autophagy (CMA) in isolated liver lysosomes. Whether this occurs in a cellular and, in particular, in a neuronal cell context is unclear. Using a mutant ASYN form that lacks the CMA recognition motif and RNA interference against the rate-limiting step in the CMA pathway, Lamp2a, we show here that CMA is indeed involved in WT ASYN degradation in PC12 and SH-SY5Y cells, and in primary cortical and midbrain neurons. However, the extent of involvement varies between cell types, potentially because of differences in compensatory mechanisms. CMA inhibition leads to an accumulation of soluble high molecular weight and detergent-insoluble species of ASYN, suggesting that CMA dysfunction may play a role in the generation of such aberrant species in PD. ASYN and Lamp2a are developmentally regulated in parallel in cortical neuron cultures and in vivo in the central nervous system, and they physically interact as indicated by co-immunoprecipitation. In contrast to previous reports, inhibition of macroautophagy, but not the proteasome, also leads to WT ASYN accumulation, suggesting that this lysosomal pathway is also involved in normal ASYN turnover. These results indicate that CMA and macroautophagy are important pathways for WT ASYN degradation in neurons and underline the importance of CMA as degradation machinery in the nervous system.
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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 [22]
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 [110]
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Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
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AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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A Third-Generation Lentivirus Vector with a Conditional Packaging System
Dull, T., Zufferey, R., Kelly, M., Mandel, R. J., Nguyen, M., Trono, D., & Naldini, L. (1998) · Journal of Virology · doi:10.1128/jvi.72.11.8463-8471.1998 · Cited by 3,341
Autophagy in Health and Disease: A Double-Edged Sword
Shintani, T., & Klionsky, D. J. (2004) · Science · doi:10.1126/science.1099993 · Cited by 2,559
Rational siRNA design for RNA interference
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Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D. (2004) · Science · doi:10.1126/science.1101738 · Cited by 2,024
Self-citationRubinson, D. A., Dillon, C. P., Kwiatkowski, A. V., Sievers, C., Yang, L., Kopinja, J. E., Rooney, D. L., Zhang, M., Ihrig, M. M., McManus, M. T., et al. (2003) · Nature Genetics · doi:10.1038/ng1117 · Cited by 1,499
Research works printed but not linked: 1
- Martinez-Vicente, 2008, J. Clin. Investig., 118, 777
Cited by
Sorted by citations
-Synuclein in Parkinson's Disease
Stefanis, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009399 · Cited by 1,446
Self-citationThe 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 1,407
Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S. D., Ntzouni, M., Margaritis, L. H., Stefanis, L., & Vekrellis, K. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5699-09.2010 · Cited by 1,115
“Cultures of rat (embryonic day 18) cortical neurons were prepared as described previously (Vogiatzi et al., 2008).”
MethodSelf-citationAutophagy 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
Ageing and Parkinson's disease: Why is advancing age the biggest risk factor?
Reeve, A. K., Simcox, E. M., & Turnbull, D. M. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.01.004 · Cited by 1,013
Metadata
- Authors
- Vogiatzi, T., Xilouri, M., Vekrellis, K., & Stefanis, L.
- Affiliations
- Biomedical Research Foundation of the Academy of Athens (GR)
- National and Kapodistrian University of Athens (GR)
- Corresponding author
- Stefanis, Leonidas
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 283
- Issue
- 35
- Pages
- 23542-23556
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2527094
- OpenAlex
- W2026175550
- Cited by
- 683
- References
- 44
- Citations by year
- 2026: 28 · 2025: 33 · 2024: 43 · 2023: 44 · 2022: 36 · 2021: 48 · 2020: 56 · 2019: 40 · 2018: 34 · 2017: 32 · 2016: 30 · 2015: 33 · 2014: 39 · 2013: 39 · 2012: 41
- FWCI
- 22.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R21NS055693)
- 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
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- alpha-synuclein, chaperone-mediated autophagy, macroautophagy, Parkinson's disease, LAMP2A, lysosomal degradation, post-transcriptional regulation, PC12 cells, SH-SY5Y cells, cortical neurons, midbrain neurons, protein turnover
- MeSH terms
- Animals, Autophagy, Cerebral Cortex, Humans, Mesencephalon, Neurons, Parkinson Disease, PC12 Cells, Rats, Wistar, Molecular Chaperones, Mice, Rats, alpha-Synuclein, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 2
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