PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.
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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.
Published Version (Please cite this version)
Dickey, Audrey S, Victor V Pineda, Taiji Tsunemi, Patrick P Liu, Helen C Miranda, Stephen K Gilmore-Hall, Nicole Lomas, Kunal R Sampat, et al. (2016). PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med, 22(1). pp. 37–45. 10.1038/nm.4003 Retrieved from https://hdl.handle.net/10161/15677.
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