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.

Disruption of microglia histone acetylation and protein pathways in mice exhibiting inflammation-associated depression-like symptoms

“…In fact, PDIA3 is used as a biomarker of microglial activation (Yoo et al, 2014); astrocytes from PARK7 knockout mice exhibit decreased neuroprotection to LPS challenge (Ashley et al, 2016); and DPYSL2 was under-abundant in the prefrontal cortex of a rat clomipramine model of depression characterized (Gellén et al, 2017). Oxidative stress has been associated with depression-related disorders and a study of oxidative stress in rat brains reported high abundance of ACTG2 and ACTG1 ACTG2 (Foley et al, 2016).…”

The reduced activity of PP-1α under redox stress condition is a consequence of GSH-mediated transient disulfide formation

“…Moreover, PP-1α was associated with oxidative brain diseases such as schizophrenia 15 , alcohol abuse induced ciliary dysfunction (AICD) 16 . Interestingly, PP-1 was found as a target of peroxide stress in the moderately oxidized brains to form transient disulfides, which may promote the slow accrual of neuronal damage that could detour healthy brain development and aging 17 . However, the underlying mechanism of how redox stress controls PP-1 activity has not been well understood.…”

Regulation of Cardiac PKA Signaling by cAMP and Oxidants

“…In brain, oxidative stress had been associated with neuronal damage and schizophrenia in earlier studies [ 183 , 184 ]. An investigation of rat brain extracts eventually identified PP1 amongst the proteins that contained disulfide bonds, which were reducible by the mild reducing agent tris(2-carboxyethyl)-phosphine (TCEP) [ 185 ]. A mass spectrometry approach that used a mechanism of data evaluation especially designed for the identification of disulfide bonds, detected interactions between Cys39-Cys127 as well as Cys127-Cys127 of recombinant PP1α with increasing concentrations of H 2 O 2 [ 186 ].…”