Oxidative Dimer Formation Is the Critical Rate-Limiting Step for Parkinson's Disease -Synuclein Fibrillogenesis
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- 作者：Sampathkumar Krishnan ; 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 ; and Jo
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：January 28, 2003
- 年：2003
- 卷：42
- 期：3
- 页码：829 - 837
- 全文大小：149K
- 年卷期：v.42,no.3(January 28, 2003)
- ISSN：1520-4995
文摘
Intraneuronal deposition of 
-synuclein as fibrils and oxidative stress are both implicated inthe pathogenesis of Parkinson's disease. We found that the critical rate-limiting step in nucleation of-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 A53Tmutant -synucleins, because of their greater propensity to self-interact, which is reflected in the smallervalues of the osmotic second virial coefficient compared to that of wild-type synuclein. Our finding thatoxidation is an essential step in -synuclein aggregation supports a mechanism of Parkinson's diseasepathogenesis in which the separately studied pathogenic factors of oxidative stress and -synucleinaggregation converge at the critical step of -synuclein dimer formation.
-synuclein as fibrils and oxidative stress are both implicated inthe pathogenesis of Parkinson's disease. We found that the critical rate-limiting step in nucleation of-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 A53Tmutant -synucleins, because of their greater propensity to self-interact, which is reflected in the smallervalues of the osmotic second virial coefficient compared to that of wild-type synuclein. Our finding thatoxidation is an essential step in -synuclein aggregation supports a mechanism of Parkinson's diseasepathogenesis in which the separately studied pathogenic factors of oxidative stress and -synucleinaggregation converge at the critical step of -synuclein dimer formation.