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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Substitution / genetics
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Chromatography, High Pressure Liquid
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Cross-Linking Reagents / metabolism
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Dimerization
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Humans
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Hydrogen-Ion Concentration
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Light
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / ultrastructure
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Osmolar Concentration
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Osmotic Pressure
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Oxidation-Reduction
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Oxidative Stress
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Parkinson Disease / etiology
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Parkinson Disease / metabolism*
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Parkinson Disease / pathology
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Scattering, Radiation
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Spectrometry, Mass, Electrospray Ionization
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Spectrophotometry, Ultraviolet
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Synucleins
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Temperature
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Tyrosine / analogs & derivatives*
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Tyrosine / metabolism
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alpha-Synuclein
Substances
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Cross-Linking Reagents
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Nerve Tissue Proteins
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Protein Isoforms
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SNCA protein, human
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Synucleins
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alpha-Synuclein
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Tyrosine
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dityrosine