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.

Abstract

Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington’s disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the U.S. Food and Drug Administration–approved drug bexarotene. We tested the therapeutic potential of bexarotene in HD and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.

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