Oxidative dimer formation is the critical rate-limiting step for Parkinson's disease alpha-synuclein fibrillogenesis.
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.
Krishnan
Sampathkumar
S
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Chi
Eva Y
EY
Wood
Stephen J
SJ
Kendrick
Brent S
BS
Li
Cynthia
C
Garzon-Rodriguez
William
W
Wypych
Jette
J
Randolph
Theodore W
TW
Narhi
Linda O
LO
Biere
Anja Leona
AL
Citron
Martin
M
Carpenter
John F
JF
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
D003432:Cross-Linking Reagents; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D014443:Tyrosine; C007543:dityrosine