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. Magnuson & 3 others Anthony 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.

LanguageEnglish (US)
Pages37-45
Number of pages9
JournalNature Medicine
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

PPAR delta
Huntington Disease
Neurons
Chemical activation
Transcriptional Activation
Trinucleotide Repeat Expansion
Neurologic Mutant Mice
Phenotype
Trinucleotide Repeats
Corpus Striatum
Neurology
Stem cells
Neurodegenerative Diseases
Cell Survival
Stem Cells
Central Nervous System
Genes
Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dickey, A. S., Pineda, V. V., Tsunemi, T., Liu, P. P., Miranda, H. C., Gilmore-Hall, S. K., ... 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. DOI: 10.1038/nm.4003

PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. / Dickey, Audrey S.; Pineda, Victor V.; Tsunemi, Taiji; Liu, Patrick P.; Miranda, Helen C.; Gilmore-Hall, Stephen K.; Lomas, Nicole; Sampat, Kunal R.; Buttgereit, Anne; Torres, Mark Joseph Manalang; Flores, April L.; Arreola, Martin; Arbez, Nicolas; Akimov, Sergey S.; Gaasterland, Terry; Lazarowski, Eduardo R.; Ross, Christopher A.; Yeo, Gene W.; Sopher, Bryce L.; Magnuson, Gavin K.; Pinkerton, Anthony B.; Masliah, Eliezer; La Spada, Albert R.

In: Nature Medicine, Vol. 22, No. 1, 01.01.2016, p. 37-45.

Research output: Contribution to journalArticle

Dickey, AS, Pineda, VV, Tsunemi, T, Liu, PP, Miranda, HC, Gilmore-Hall, SK, Lomas, N, Sampat, KR, Buttgereit, A, Torres, MJM, Flores, AL, Arreola, M, Arbez, N, Akimov, SS, Gaasterland, T, Lazarowski, ER, Ross, CA, Yeo, GW, Sopher, BL, Magnuson, GK, Pinkerton, AB, Masliah, E & La Spada, AR 2016, 'PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically' Nature Medicine, vol 22, no. 1, pp. 37-45. DOI: 10.1038/nm.4003
Dickey AS, Pineda VV, Tsunemi T, Liu PP, Miranda HC, Gilmore-Hall SK et al. PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nature Medicine. 2016 Jan 1;22(1):37-45. Available from, DOI: 10.1038/nm.4003
Dickey, Audrey S. ; Pineda, Victor V. ; Tsunemi, Taiji ; Liu, Patrick P. ; Miranda, Helen C. ; Gilmore-Hall, Stephen K. ; Lomas, Nicole ; Sampat, Kunal R. ; Buttgereit, Anne ; Torres, Mark Joseph Manalang ; Flores, April L. ; Arreola, Martin ; Arbez, Nicolas ; Akimov, Sergey S. ; Gaasterland, Terry ; Lazarowski, Eduardo R. ; Ross, Christopher A. ; Yeo, Gene W. ; Sopher, Bryce L. ; Magnuson, Gavin K. ; Pinkerton, Anthony B. ; Masliah, Eliezer ; La Spada, Albert R./ PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. In: Nature Medicine. 2016 ; Vol. 22, No. 1. pp. 37-45
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