title: Disulfide Stress Targets Modulators of Excitotoxicity in Otherwise Healthy Brains.
abstract: Oxidative stress is a long-hypothesized cause of diverse neurological and psychiatric disorders but the pathways by which physiological redox perturbations may detour healthy brain development and aging are unknown. We reported recently (Foley et al., Neurochem Res 39:2030-2039, 2014) that two-electron oxidations, to disulfides, of protein vicinal thiols can vary markedly in association with more modest oxidations of the glutathione redox couple in brains from healthy adolescent rats whereas levels of protein S-glutathionylation were low and unchanged. Here, we demonstrate that the selective oxidations of protein vicinal thiols, occurring only in the more oxidized brains under study, were linked specifically to a peroxide stress as evidenced by increased oxidations, to disulfides, of the presumed catalytic vicinal thiols of peroxiredoxins 1 and 2. Moreover, we identify the catalytic subunit(s) of Na+, K+-ATPase, tubulins, glyceraldehyde-3-phosphate dehydrogenase, and protein phosphatase 1, all of which can modulate glutamate neurotransmission and the vulnerability of neurons to excitotoxicity, as non-peroxidase proteins exhibiting prominent oxidations of vicinal thiols. The two-electron pathway, demonstrated here, linking physiological redox perturbations in otherwise healthy brains to protein determinants of excitotoxicity, suggests an alternative to free radical pathways by which oxidative stress may impact brain development and aging.
authors.affiliation: Biochemistry Program, Department of Chemistry, University of Scranton, 800 Linden St., Scranton, PA, 18510, USA. foleyt2@scranton.edu.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Foley
authors.affiliation: Biochemistry Program, Department of Chemistry, University of Scranton, 800 Linden St., Scranton, PA, 18510, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Katchur
authors.affiliation: Biochemistry Program, Department of Chemistry, University of Scranton, 800 Linden St., Scranton, PA, 18510, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D054464:Peroxiredoxins / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D004220:Disulfides; D005609:Free Radicals; D013438:Sulfhydryl Compounds; D054464:Peroxiredoxins; D019803:Glutathione Disulfide
keywords: Excitotoxicity; Glyceraldehyde-3-phosphate dehydrogenase; Na+, K+-ATPase; Oxidative stress; Protein disulfides; Protein phosphatase 1; Thiol redox; Tubulin