Glutathione peroxidase 4: a new player in neurodegeneration?

Abstract

Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme reported as an inhibitor of ferroptosis, a recently discovered non-apoptotic form of cell death. This pathway was initially described in cancer cells and has since been identified in hippocampal and renal cells. In this Perspective, we propose that inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration. In addition, we suggest that selenium deficiency enhances susceptibility to ferroptotic processes, as well as other programmed cell death pathways due to a reduction in GPx4 activity. We review recent studies of GPx4 with an emphasis on neuronal protection, and discuss the relevance of selenium levels on its enzymatic activity.

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

“…Indeed, NADPH levels are a biomarker of ferroptosis sensitivity across many cancer cell lines (Shimada et al, 2016a). Selenium is required for the biosynthesis of GPX4, which has an active-site selenocysteine (Cardoso et al, 2017). Thus, selenium supplementation promotes ferroptosis resistance, while selenium depletion promotes ferroptosis sensitivity, presumably by modulating GPX4 abundance and activity (Cardoso et al, 2017).…”

“…Selenium is required for the biosynthesis of GPX4, which has an active-site selenocysteine (Cardoso et al, 2017). Thus, selenium supplementation promotes ferroptosis resistance, while selenium depletion promotes ferroptosis sensitivity, presumably by modulating GPX4 abundance and activity (Cardoso et al, 2017). A number of other genes have been implicated as modulators of sensitivity to ferroptosis or markers of ferroptosis in diverse contexts: SAT1 , which lies downstream of p53 (Ou et al, 2016) is involved in polyamine metabolism; kiss of death (KOD) in Arabidopsis (Distefano et al, 2017) and FANCD2 in bone marrow stromal cells are induced during ferroptosis (Song et al, 2016); TTC35 , CS , ATP5G3 , and RPL8 are involved in diverse processes in human cancer cells and suppress erastin-induced ferroptosis upon knockdown (Dixon et al, 2012).…”

Regulation of lipid peroxidation and ferroptosis in diverse species

“…The compound FIN56 depletes mevalonatederived CoQ 10 by modulating squalene synthase (SQS; encoded by the FDFT1 gene) (Shimada et al 2016b); statin drugs inhibit HMG CoA reductase (HMGCR), also depleting CoQ 10 and inhibiting tRNA isopentenylation via TRIT1, needed for maturation of GPX4 (Fradejas et al 2013;Shimada et al 2016b;Viswanathan et al 2017). Ferroptosis sensitivity is also impacted by the NADPH and selenium metabolism pathways (Shimada et al 2016a;Cardoso et al 2017) as well as kiss of death (KOD) in Arabidopsis (Distefano et al 2017). Orthologs of these genes may modulate ferroptosis sensitivity in numerous species.…”

Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer's Disease

“…Our observations are consistent with 2 potential fates for sodium selenate: (i) reduction to selenite, according to a pathway previously identified in the gut [41]; and (ii) direct incorporation into selenoproteins that cross the blood-brain barrier, which would support efficiency of this compound in promoting antioxidant activity in the CNS. While selenoprotein P is the master regulator of selenium delivery to the CNS [42], glutathione peroxidase 4 (GPx4) is the most abundant selenoprotein in brain, and has recently garnered attention as an important regulator of ferroptosis [43], a newly identified form of iron-dependent programmed cell death that causes aggressive lipid peroxidation [44,45] thought to play a major role in AD pathology [46]. Since AD-affected brain tissue has lower levels of selenium [6,10] and selenium supplementation has been shown to directly interdict amyloid and iron neurotoxicity by modulating GPx activity [47], GPx4 expression and activity may suffer from insufficient selenium supply, and on this basis, supplementation trials are worth exploring.…”