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

• Published in: Biochemistry (Easton) Vol. 42; no. 3; pp. 829 - 837
• Main Authors: Krishnan, Sampathkumar, Chi, Eva Y, Wood, Stephen J, Kendrick, Brent S, Li, Cynthia, Garzon-Rodriguez, William, Wypych, Jette, Randolph, Theodore W, Narhi, Linda O, Biere, Anja Leona, Citron, Martin, Carpenter, John F
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.01.2003
• Subjects: alpha-Synuclein; Amino Acid Substitution - genetics; Chromatography, High Pressure Liquid; Cross-Linking Reagents - metabolism; Dimerization; Humans; Hydrogen-Ion Concentration; Light; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - ultrastructure; Osmolar Concentration; Osmotic Pressure; Oxidation-Reduction; Oxidative Stress; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Protein Isoforms - genetics; Protein Isoforms - metabolism; Scattering, Radiation; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrophotometry, Ultraviolet; Synucleins; Temperature; Tyrosine - analogs & derivatives; Tyrosine - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi026528t

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.