Defeating neurotoxicity with a repurposed drug
PPARδ is a permissive nuclear receptor that heterodimerizes with the retinoid X receptor (RXR) to activate target genes. Interference with transcription of PPARδ target genes contributes to neurodegeneration in Huntington’s disease (HD). In new work, Dickey et al. evaluated the RXR agonist bexarotene in cellular models of HD and in an HD mouse model. They determined that bexarotene was effective at countering HD neurotoxicity in mouse primary neurons, human HD patient stem cell–derived neurons, and the BAC-HD mouse model. The authors then examined the basis for PPARδ’s neuroprotective effect and found that treatment with RXR/PPARδ agonists enhanced oxidative metabolism, promoted mitochondrial quality control, and boosted protein homeostasis by activating autophagy.
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