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Nat Med. 2016 Jan;22(1):37-45. doi: 10.1038/nm.4003. Epub 2015 Dec 7.

PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.

Author information

1
Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
2
Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
3
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.
4
Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.
5
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA.
6
Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
7
Scripps Institute for Oceanography, University of California San Diego, La Jolla, California, USA.
8
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
10
Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
11
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
12
Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA.
13
Department of Pathology, University of California San Diego, La Jolla, California, USA.
14
Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
15
Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
16
Rady Children's Hospital, San Diego, California, USA.

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.

PMID:
26642438
PMCID:
PMC4752002
DOI:
10.1038/nm.4003
[Indexed for MEDLINE]
Free PMC Article

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