Cited by 683Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyLysosomal Storage Disorders Research

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Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells

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Vogiatzi, Tereza, Xilouri, Maria, Vekrellis, Kostas, Stefanis, Leonidas·2008·Journal of Biological Chemistry

DOI 10.1074/jbc.m801992200PMC PMC2527094

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Abstract

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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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
ORCID: Xilouri, Maria
Vekrellis, Kostas
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)
DOI: 10.1074/jbc.m801992200
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4445 d)
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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Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells

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