Targeting brain redox homeostasis as a therapeutic approach in Huntington's disease models

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease, which is caused by an abnormal CAG-repeat expansion within huntingtin gene. Oxidative stress is a pervasive feature in HD. Many antioxidant therapies have shown merely marginal or no beneficial effects in HD clinical trials. Therefore, targeting specific pathways that are involved in redox homeostasis and that are disrupted in HD might be protective. Here I use two approaches to modulate the brain redox status and investigate their effects on HD models. Firstly, I screened from a series of thiol-disulfide oxidoreductases in cultured cells, and identified thioredoxin 1 (TXN1) and thioredoxin-related transmembrane protein 3 (TXNDC10) as candidates that decreasing mutant huntingtin levels. The following in vivo study has shown the neuroprotective effects of TXN1 and TXNDC10 by a lentiviral delivery approach. Secondly, I studied the effects of dietary selenium supplementation in HD transgenic mice and further investigated the underlying mechanisms. I found that the neuroprotective effect of selenium is correlated with increased transcripts level of selenoprotein glutathione peroxidase 3 (Gpx3). Our findings suggest that these two approaches that modulating redox homeostasis might serve as potential therapeutic treatment for HD.