Cited by 326Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyAlzheimer's disease research and treatments

Lewy Body-like α-Synuclein Aggregates Resist Degradation and Impair Macroautophagy

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Tanik, Selcuk A., Schultheiss, Christine E., Volpicelli-Daley, Laura A., Brunden, Kurt R., Lee, Virginia M.Y.·2013·Journal of Biological Chemistry

Abstract

Cytoplasmic α-synuclein (α-syn) aggregates, referred to as Lewy bodies, are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson disease. Activation of macroautophagy is suggested to facilitate degradation of certain proteinaceous inclusions, but it is unclear if this pathway is capable of degrading α-syn aggregates. Here, we examined this issue by utilizing cellular models in which intracellular Lewy body-like α-syn inclusions accumulate after internalization of pre-formed α-syn fibrils into α-syn-expressing HEK293 cells or cultured primary neurons. We demonstrate that α-syn inclusions cannot be effectively degraded, even though they co-localize with essential components of both the autophagic and proteasomal protein degradation pathways. The α-syn aggregates persist even after soluble α-syn levels have been substantially reduced, suggesting that once formed, the α-syn inclusions are refractory to clearance. Importantly, we also find that α-syn aggregates impair overall macroautophagy by reducing autophagosome clearance, which may contribute to the increased cell death that is observed in aggregate-bearing cells. Background: α-Synuclein aggregates and macroautophagy are associated with neurodegeneration. Results: Modulation of macroautophagic activity does not affect α-synuclein aggregate levels, although these aggregates cause accumulation of immature autophagosomes. Conclusion: α-Synuclein aggregates are resistant to degradation and impair autophagy by delaying autophagosome maturation. Significance: Understanding the impact of α-synuclein aggregates on autophagy may help elucidate therapies for α-synuclein-mediated neurodegeneration.

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Authors
Tanik, S. A., Schultheiss, C. E., Volpicelli-Daley, L. A., Brunden, K. R., & Lee, V. M. Y.
Affiliations
University of Pennsylvania (US)
Corresponding author
Lee, Virginia M.Y.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2013-05
Volume
288
Issue
21
Pages
15194-15210
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2017642230
Cited by
326
References
83
Citations by year
2026: 17 · 2025: 23 · 2024: 25 · 2023: 11 · 2022: 27 · 2021: 28 · 2020: 40 · 2019: 40 · 2018: 28 · 2017: 26 · 2016: 23 · 2015: 18 · 2014: 15 · 2013: 5
FWCI
12.91
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cedars-Sinai Medical Center
  • National Institutes of Health (NS053488)
  • National Institute of Neurological Disorders and Stroke (NS053488, P50NS053488)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
alpha-synuclein, Lewy bodies, macroautophagy, autophagosome maturation, Parkinson's disease, neurodegeneration, proteasomal degradation, autophagy dysfunction, neuronal cell death
MeSH terms
Animals, Autophagy, HeLa Cells, Humans, Models, Biological, Neurons, Parkinson Disease, Lewy Bodies, Proteasome Endopeptidase Complex, Mice, alpha-Synuclein, HEK293 Cells, Proteolysis

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