Oxidative Modifications of α‐Synuclein

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Abstract
Abstract: Hallmark lesions of neurodegenerative synucleinopathies contain α‐synuclein (α‐syn) that is modified by nitration of tyrosine residues and possibly by dityrosine cross‐linking to generated stable oligomers. Data gathered from in vitro experiments and from model systems of cells transfected with wild‐type and mutant α‐syn revealed that conditions resulting in α‐syn nitration also induce formation of α‐syn inclusions with similar biochemical characteristics to protein extracted from human lesions. The detection of tyrosine‐nitrated α‐syn signifies the formation of reactive nitrogen species capable of both radical and electrophilic attack on aromatic residues as well as nucleophilic additions and oxidations. The cellular sources and biochemical reactivity of reactive nitrogen species in the central nervous system remain largely unknown, but kinetically fast reactions of nitric oxide with superoxide to form peroxynitrite as well as enzymatic one‐electron oxidation of nitrite are two important sources of reactive nitrogen species. Based on these findings a model is proposed where the process of fibrilization can be differentially affected by oxidants and nitrating species. Posttranslational modifications of α‐syn by reactive nitrogen species inhibits fibril formation and results in urea‐ and SDS‐ insoluble, protease‐resistant α‐syn aggregates that maybe responsible for cellular toxicity.

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