Ppar-Delta 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-delta) interacts with HTT and that mutant HTT represses PPAR-delta-mediated transactivation. Increased PPAR-delta transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-delta 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-delta 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-delta using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-delta 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-delta activation may be beneficial in HD and related disorders.