Bicarbonate enhances alpha-synuclein oligomerization and nitration: intermediacy of carbonate radical anion and nitrogen dioxide radical. Biochem J 2004 Mar 01;378(Pt 2):435-47
Date
12/03/2003Pubmed ID
14640973Pubmed Central ID
PMC1223984DOI
10.1042/BJ20031466Scopus ID
2-s2.0-1642318678 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
alpha-Synuclein, a neuronal presynaptic protein, has been reported to undergo oligomerization to form toxic Lewy bodies in neurodegenerative disorders. One of the proposed mechanisms for aggregation of alpha-synuclein involves oxidative and nitrative modifications. In the present study, we show that addition of 3-morpholino-sydnonimine chloride (SIN-1) or slow infusion of pre-formed peroxynitrite (ONOO-) to mixtures containing alpha-synuclein and HCO3- markedly enhanced both nitration and aggregation of alpha-synuclein through dityrosine formation. Bicarbonate-dependent peroxidase activity of Cu,Zn-superoxide dismutase (SOD1) also induced covalent aggregation of alpha-synuclein via a CO3*--dependent mechanism. Nitrone spin traps completely inhibited CO3*--mediated oxidation/nitration and aggregation of alpha-synuclein. Conversely, alpha-synuclein inhibited CO3*--induced spin adduct formation. Independent evidence for CO3*--mediated oxidation and dimerization of alpha-synuclein was obtained from UV photolysis of [(NH3)5CoCO3]+, which generates authentic CO3*-. Irradiation of [(NH3)5CoCO3]+ and NO2- in the presence of alpha-synuclein yielded nitration and aggregation products that were similar to those obtained from a SIN-1 (or slowly infused ONOO-) and HCO3- or a myeloperoxidase/H2O2/NO2- system. Hydrophobic membranes greatly influenced alpha-synuclein aggregation and nitration in these systems. We conclude that both CO3*- and NO2* could play a major role in the nitration/aggregation of alpha-synuclein.
Author List
Andrekopoulos C, Zhang H, Joseph J, Kalivendi S, Kalyanaraman BAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnionsBicarbonates
Cyclic N-Oxides
Dimerization
Free Radicals
Hydrogen Peroxide
Hydroxylation
Liposomes
Nerve Tissue Proteins
Nitric Oxide Donors
Nitrogen Dioxide
Nitrogen Oxides
Oxidation-Reduction
Peroxidase
Peroxynitrous Acid
Reactive Nitrogen Species
Spin Labels
Superoxide Dismutase
Superoxide Dismutase-1
Synucleins
Tyrosine
alpha-Synuclein