Mice Deficient in Cellular Glutathione Peroxidase Show Increased Vulnerability to Malonate, 3-Nitropropionic Acid, and 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine

Abstract

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

“…Interestingly, PLA2 knockout mice are protected from MPTP toxicity (61), and the PLA2 inhibitor, mepacrine, also prevents the toxin-induced DA depletion in rat striatum (62). All these data indicate that NO and AA are implicated in the degeneration of a nigro striatal system in rodents.…”

Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons

“…10 B, C). Instead, the lower levels of ␣-synuclein may protect against the toxicity associated with decreased fission, as in other cases of compromised mitochondrial function (Klivenyi et al, 2000;Dauer et al, 2002). …”

“…Because electrophysiologically distinct subsets of midbrain DA neurons exist (Lammel et al, 2008(Lammel et al, , 2011, we aimed to determine whether the surviving Drp1KO DA neurons represent one of these subsets by using whole-cell recordings in horizontal brain slices. We identified surviving neurons scattered throughout the VTA and SNc as DA or non-DA during recording by visually detecting tdTomato expression.…”

Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington’s disease

“…Our screen used constitutively expressing lentiviruses to target all striatal cells, but increased cellular specificity could be achieved through use of conditional systems such as the TVA/EnvA system (18). The gene identified in our screen as enhancing the toxicity of mutant huntingtin when knocked down, Gpx6, is particularly appealing given the abundant literature linking oxidative stress to Huntington's disease pathophysiology (19), a study reporting that mice deficient in cellular glutathione peroxidase show enhanced vulnerability to a chemical model of Huntington's disease (20), a recent study identifying glutathione peroxidase activity as a suppressor of mutant Huntingtin toxicity in yeast (21), and a study reporting Gpx6 protein levels to be altered in the striatum of human Huntington's disease patients (22). Furthermore, blood-brain barrier-penetrant, orally active glutathione peroxidase-mimicking hydrogen peroxide scavengers have been identified (23,24).…”