PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.
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.
Dickey, AS; Pineda, VV; Tsunemi, T; Liu, PP; Miranda, HC; Gilmore-Hall, SK; Lomas, N; Sampat, KR; Buttgereit, A; Torres, M-JM; 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
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