Research ArticleHuntington’s Disease

PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis

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Science Translational Medicine  06 Dec 2017:
Vol. 9, Issue 419, eaal2332
DOI: 10.1126/scitranslmed.aal2332

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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.