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Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease
Abstract
Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in alpha-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.
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“It is estimated that up to 80% of dopaminergic cells in the nigro-striatal system are lost before the cardinal motor features of PD start to appear (Chung et al. 2001).”
From The clinical symptoms of Parkinson's disease. (2016) · cites this paper as Chung et al. 2001
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- Chung, K.K.K., Dawson, V.L. & Dawson, T.M. The role of the ubiquitin proteasomal pathway in Parkinson's disease and other neurogenerative diseases. Trends Neurosci. (in the press).
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Metadata
- Authors
- Chung, K. K. K., Zhang, Y., Lim, K. L., Tanaka, Y., Huang, H., Gao, J., Ross, C. A., Dawson, V. L., & Dawson, T. M.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Dawson, Ted M.
- Venue
- Nature Medicine
- Published
- 2001-10
- Volume
- 7
- Issue
- 10
- Pages
- 1144-1150
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1529474377
- Cited by
- 750
- References
- 47
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 22 · 2022: 11 · 2021: 23 · 2020: 18 · 2019: 12 · 2018: 14 · 2017: 21 · 2016: 22 · 2015: 20 · 2014: 17 · 2013: 17 · 2012: 27
- FWCI
- 42.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- National University of Singapore (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 38377, P50NS038377)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkin, synphilin-1, alpha-synuclein, ubiquitination, Lewy bodies, Parkinson's disease, familial Parkinson's disease, protein-protein interaction, ubiquitin-positive inclusions, parkin mutations, alpha-synuclein mutations
- MeSH terms
- Animals, Carrier Proteins, Cell Line, Glycosylation, Humans, Ligases, Nerve Tissue Proteins, Parkinson Disease, Ubiquitins, Mutagenesis, Lewy Bodies, Ubiquitin-Protein Ligases, Rats, Synucleins, alpha-Synuclein
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