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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

12/03/2003

Pubmed ID

14640973

Pubmed Central ID

PMC1223984

DOI

10.1042/BJ20031466

Scopus ID

2-s2.0-1642318678 (requires institutional sign-in at Scopus site)   37 Citations

Abstract

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 B

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anions
Bicarbonates
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