Superoxide is the critical driver of DOPAL autoxidation, lysyl adduct formation, and crosslinking of α-synuclein

Parkinson's disease has long been associated with redox imbalance and oxidative stress in dopaminergic neurons. The catecholaldehyde hypothesis proposes that 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate product of dopamine catabolism, is a central nexus in a network of pathways leading...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2017-05, Vol.487 (2), p.281-286
Main Authors: Werner-Allen, Jon W., Levine, Rodney L., Bax, Ad
Format: Article
Language:English
Subjects:
3,4-Dihydroxyphenylacetic Acid - analogs & derivatives
3,4-Dihydroxyphenylacetic Acid - chemistry
alpha-Synuclein - chemistry
Amyloid disease
Binding Sites
Covalent crosslinking
Cross-Linking Reagents
Enzyme Activation
Lysine
Mitochondrial impairment
Oxidation-Reduction
Oxidative stress
Oxygen - chemistry
Parkinson's disease
Protein Binding
Pyrroles - chemistry
Reactive oxygen species
Reactive Oxygen Species - chemistry
Superoxide Dismutase - chemistry
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Summary:Parkinson's disease has long been associated with redox imbalance and oxidative stress in dopaminergic neurons. The catecholaldehyde hypothesis proposes that 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate product of dopamine catabolism, is a central nexus in a network of pathways leading to disease-state neurodegeneration, owing to its toxicity and potent ability to oligomerize α-synuclein, the main component of protein aggregates in Lewy bodies. In this work we examine the connection between reactive oxygen species and DOPAL autoxidation. We show that superoxide propagates a chain reaction oxidation, and that this reaction is dramatically inhibited by superoxide dismutase. Moreover, superoxide dismutase prevents DOPAL from forming dicatechol pyrrole adducts with lysine and from covalently crosslinking α-synuclein. Given that superoxide is a major radical byproduct of impaired cellular respiration, our results provide a possible mechanistic link between mitochondrial dysfunction and synuclein aggregation in dopaminergic neurons. [Display omitted] •Superoxide dismutase (SOD) inhibits the autoxidation of DOPAL.•SOD prevents DOPAL from forming dicatechol pyrrole lysine adducts.•SOD inhibits DOPAL-mediated crosslinking of a-synuclein.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2017.04.050