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PPAR? activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis.

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 PPAR? 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 PPAR? agonist KD3010 is an effective therapy for HD in a mouse model. PPAR? forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPAR? 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 PPAR? 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 PPAR? agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPAR? activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.

SUBMITTER: Dickey AS

PROVIDER: S-EPMC5748332 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Dickey Audrey S AS Sanchez Dafne N DN Arreola Martin M Sampat Kunal R KR Fan Weiwei W Arbez Nicolas N Akimov Sergey S Van Kanegan Michael J MJ Ohnishi Kohta K Gilmore-Hall Stephen K SK Flores April L AL Nguyen Janice M JM Lomas Nicole N Hsu Cynthia L CL Lo Donald C DC Ross Christopher A CA Masliah Eliezer E Evans Ronald M RM La Spada Albert R AR

Science translational medicine 20171201 419

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 huntin ...[more]

PMID: 29212711

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Project description:Recent studies suggest cone degeneration in retinitis pigmentosa (RP) may result from intracellular energy depletion. We tested the hypothesis that cones die when depleted of energy by examining the effect of two bioenergetic, nutraceutical agents on cone survival. The study had three specific aims: firstly, we, studied the neuroprotective efficacies of glucose and creatine in an in vitro model of RP. Next, we utilized a well-characterized mouse model of RP to examine whether surviving cones, devoid of their inner segments, continue to express genes vital for glucose, and creatine utilization. Finally, we analyzed the neuroprotective properties of glucose and creatine on cone photoreceptors in a mouse model of RP. Two different bioenergy-based therapies were tested in rd1 mice: repeated local delivery of glucose and systemic creatine. Optomotor responses were tested and cone density was quantified on retinal wholemounts. The results showed that glucose supplementation increased survival of cones in culture subjected to mitochondrial stress or oxidative insult. Despite losing their inner segments, surviving cones in the rd1 retina continued to express the various glycolytic enzymes. Following a single subconjunctival injection, the mean vitreous glucose concentration was significantly elevated at 1 and 8 h, but not at 16 h after injection; however, daily subconjunctival injection of glucose neither enhanced spatial visual performance nor slowed cone cell degeneration in rd1 mice relative to isotonic saline. Creatine dose-dependently increased survival of cones in culture subjected to mitochondrial dysfunction, but not to oxidative stress. Despite the loss of their mitochondrial-rich inner segments, cone somas and axonal terminals in the rd1 retina were strongly positive for both the mitochondrial and cytosolic forms of creatine kinase at each time point examined. Creatine-fed rd1 mice displayed enhanced optomotor responses compared to mice fed normal chow. Moreover, cone density was significantly greater in creatine-treated mice compared to controls. The overall results of this study provide tentative support for the hypothesis that creatine supplementation may delay secondary degeneration of cones in individuals with RP.

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PPAR? activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis.

Publications

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

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