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 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 [22]
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 [110]
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- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › 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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