| Ubiquitination of alpha-synuclein. | |
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MedLine Citation:
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PMID: 15628878 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Filamentous alpha-synuclein depositions are the defining hallmarks of a subset of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. We previously reported that alpha-synuclein in those brains are extensively phosphorylated at Ser129 [Fujiwara et al. (2002) Nat. Cell Biol. 4, 160-164] and also partially ubiquitinated [Hasegawa et al. (2002) J. Biol. Chem. 277, 49071-49076]. Here, we investigate ubiquitination of alpha-synuclein in vitro and in vivo and report the ubiquitination sites and the effects of familial PD-linked mutations, phosphorylation, and fibril formation on ubiquitination. Protein-sequence analysis revealed that Lys21, Lys23, Lys32, and Lys34 within the repeats in the amino-terminal half are liable to ubiquitination in vitro. A site-directed mutagensis study confirmed that these are the major ubiquitination sites. A53T and A30P mutations had no significant effect on ubiquitination. Similarly, phosphorylation of alpha-synuclein at Ser129 did not affect ubiquitination. Notably, we show that assembled, filamentous alpha-synuclein is less ubiquitinated than the soluble form and that the major ubiquitination sites are localized to Lys6, Lys10, and Lys12 at the amino-terminal region of filamentous alpha-synuclein. Furthermore, we successfully detected ubiquitination of alpha-synuclein in 293T cells by cotransfection with alpha-synuclein and ubiquitin. The in vivo ubiquitination sites were found to be identical to those in filamentous alpha-synuclein. PD-linked mutations and phosphorylation at Ser129 had no effects on ubiquitination of alpha-synuclein in vivo. These data may have implications for the mechanisms of the formation of alpha-synuclein deposits in alpha-synucleinopathy brains. |
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Authors:
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Takashi Nonaka; Takeshi Iwatsubo; Masato Hasegawa |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biochemistry Volume: 44 ISSN: 0006-2960 ISO Abbreviation: Biochemistry Publication Date: 2005 Jan |
Date Detail:
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Created Date: 2005-01-04 Completed Date: 2005-03-04 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0370623 Medline TA: Biochemistry Country: United States |
Other Details:
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Languages: eng Pagination: 361-8 Citation Subset: IM |
Affiliation:
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Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Binding Sites Brain / metabolism Cell Line Humans Kidney Mutation Nerve Tissue Proteins / metabolism* Parkinson Disease / genetics Synucleins Ubiquitin / chemistry, genetics*, metabolism* alpha-Synuclein |
| Chemical | |
Reg. No./Substance:
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0/Nerve Tissue Proteins; 0/SNCA protein, human; 0/Synucleins; 0/Ubiquitin; 0/alpha-Synuclein |
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