Thiol-disulfide Oxidoreductases TRX1 and TMX3 Decrease Neuronal Atrophy in a Lentiviral Mouse Model of Huntington’s Disease

Discussion Abnormal redox homeostasis and oxidative stress are consistent features of human HD and cell-based and animal models45,46. Identification of appropriate targets for modulation of redox homeostasis could provide novel therapeutic approaches for treating HD. Protein thiols are an important site of post-translational modification involved in the regulation of redox responsive cell signaling processes24. Oxidative stress can result in increased protein thiol oxidation and disruption of these homeostatic processes, potentially contributing to cell dysfunction and degeneration. Transgenic mice expressing the N171 mHTT protein fragment develop a phenotype similar to human HD including striatal atrophy47. We have shown that the N171 fragment of HTT can form thiol-dependent oligomers which are degraded more slowly than a N171 protein variant that lacks thiols and is unable to oligomerize6. Numerous proteins with thiol-disulfide oxidoreductase activity exist that facilitate the reduction of oxidized protein thiols in cells24. Here we sought to identify if there are thiol-disulfide oxidoreductase enzymes that can decrease mHTT levels in cells and provide protection against neuronal atrophy in HD mice. We tested a representative set of thiol-disulfide oxidoreductases for mHTT decreasing effects. We used primary and secondary cell-based screens to identify candidate genes for testing in HD mice (Fig. 1). Based on our previous findings6 enzymatic conversion of mHTT oligomer to m...
Source: PLOS Currents Huntington Disease - Category: Neurology Authors: Source Type: research