Oxidative modifications of alpha-synuclein.
Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein (alpha-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 alpha-syn revealed that conditions resulting in alpha-syn nitration also induce formation of alpha-syn inclusions with similar biochemical characteristics to protein extracted from human lesions. The detection of tyrosine-nitrated alpha-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 alpha-syn by reactive nitrogen species inhibits fibril formation and results in urea- and SDS- insoluble, protease-resistant alpha-syn aggregates that maybe responsible for cellular toxicity.
Ischiropoulos
Harry
H
Stokes Research Institute, Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ischirop@mail.med.upenn.edu
D000818:Animals; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D009566:Nitrates; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein