| Literature DB >> 12534296 |
Sampathkumar Krishnan1, Eva Y Chi, Stephen J Wood, Brent S Kendrick, Cynthia Li, William Garzon-Rodriguez, Jette Wypych, Theodore W Randolph, Linda O Narhi, Anja Leona Biere, Martin Citron, John F Carpenter.
Abstract
Intraneuronal deposition of alpha-synuclein as fibrils and oxidative stress are both implicated in the pathogenesis of Parkinson's disease. We found that the critical rate-limiting step in nucleation of alpha-synuclein fibrils under physiological conditions is the oxidative formation and accumulation of a dimeric, dityrosine cross-linked prenucleus. Dimer formation is accelerated for the pathogenic A30P and A53T mutant alpha-synucleins, because of their greater propensity to self-interact, which is reflected in the smaller values of the osmotic second virial coefficient compared to that of wild-type synuclein. Our finding that oxidation is an essential step in alpha-synuclein aggregation supports a mechanism of Parkinson's disease pathogenesis in which the separately studied pathogenic factors of oxidative stress and alpha-synuclein aggregation converge at the critical step of alpha-synuclein dimer formation.Entities:
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Year: 2003 PMID： 12534296 DOI： 10.1021/bi026528t
Source DB: PubMed Journal: Biochemistry ISSN： 0006-2960 Impact factor: 3.162