title: Oxidative dimer formation is the critical rate-limiting step for Parkinson's disease alpha-synuclein fibrillogenesis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Sampathkumar
authors.initials: S
authors.lastname: Krishnan
authors.forename: Eva Y
authors.initials: EY
authors.lastname: Chi
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wood
authors.forename: Brent S
authors.initials: BS
authors.lastname: Kendrick
authors.forename: Cynthia
authors.initials: C
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Garzon-Rodriguez
authors.forename: Jette
authors.initials: J
authors.lastname: Wypych
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Randolph
authors.forename: Linda O
authors.initials: LO
authors.lastname: Narhi
authors.forename: Anja Leona
authors.initials: AL
authors.lastname: Biere
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.forename: John F
authors.initials: JF
authors.lastname: Carpenter
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008027:Light; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012542:Scattering, Radiation; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013056:Spectrophotometry, Ultraviolet; D051843:Synucleins; D013696:Temperature; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D051844:alpha-Synuclein
chemical_list: D003432:Cross-Linking Reagents; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D014443:Tyrosine; C007543:dityrosine