The DOI matches its Crossref record; 83 of the 83 references it cites were found in a registry or an index.
Lewy Body-like α-Synuclein Aggregates Resist Degradation and Impair Macroautophagy
Open accessAbstract
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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“Furthermore, LB-like synuclein aggregates resist degradation and impair autophagy20.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [20]
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Metadata
- 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)
- PMC
- PMC3663539
- 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
- hybrid
- doi.org
- Licence
- 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 › 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, 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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