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

Audrey S. Dickey, Victor V. Pineda, Taiji Tsunemi, Patrick P. Liu, Helen C. Miranda, Stephen K. Gilmore-Hall, Nicole Lomas, Kunal R. Sampat, Anne Buttgereit, Mark Joseph Manalang Torres, April L. Flores, Martin Arreola, Nicolas Arbez, Sergey S. Akimov, Terry Gaasterland, Eduardo R. Lazarowski, Christopher A. Ross, Gene W. Yeo, Bryce L. Sopher, Gavin K. MagnusonAnthony B. Pinkerton, Eliezer Masliah, Albert R. La Spada

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)37-45
Number of pages9
JournalNature medicine
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Dickey, A. S., Pineda, V. V., Tsunemi, T., Liu, P. P., Miranda, H. C., Gilmore-Hall, S. K., Lomas, N., Sampat, K. R., Buttgereit, A., Torres, M. J. M., Flores, A. L., Arreola, M., Arbez, N., Akimov, S. S., Gaasterland, T., Lazarowski, E. R., Ross, C. A., Yeo, G. W., Sopher, B. L., ... La Spada, A. R. (2016). PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nature medicine, 22(1), 37-45. https://doi.org/10.1038/nm.4003