Format

Send to

Choose Destination
Sci Transl Med. 2017 Dec 6;9(419). pii: eaal2332. doi: 10.1126/scitranslmed.aal2332.

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

Author information

1
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
2
Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, USA.
3
Departments of Psychiatry, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4
Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
5
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
6
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
7
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
8
Howard Hughes Medical Institute, Salk Institute for Biological Studies, San Diego, CA 92037, USA.
9
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. alaspada@ucsd.edu.
10
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
11
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
12
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
13
Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

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.

PMID:
29212711
PMCID:
PMC5748332
DOI:
10.1126/scitranslmed.aal2332
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center