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Oxidative Dimer Formation Is the Critical Rate-Limiting Step for Parkinson's Disease α-Synuclein Fibrillogenesis†

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Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, Department of Chemical Engineering, University of Colorado, Boulder, Colorado 80309, and Amgen, Inc., Thousand Oaks, California 91320
Cite this: Biochemistry 2003, 42, 3, 829–837
Publication Date (Web):December 20, 2002
https://doi.org/10.1021/bi026528t
Copyright © 2003 American Chemical Society
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    Abstract

    Intraneuronal deposition of α-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 α-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 α-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 α-synuclein aggregation supports a mechanism of Parkinson's disease pathogenesis in which the separately studied pathogenic factors of oxidative stress and α-synuclein aggregation converge at the critical step of α-synuclein dimer formation.

    †

     Supported by National Science Foundation Grant BES 0138595 to J.F.C. and T.W.R.

    ‡

     University of Colorado Health Sciences Center.

    §

     University of Colorado.

    ‖

     Amgen, Inc.

    *

     To whom correspondence should be addressed:  Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262. Phone:  (303) 315-6074. Fax:  (303) 315-6281. E-mail:  [email protected].

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