|Title||PPAR-delta is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||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.JM, Flores A.L, Arreola M., Arbez N., Akimov S.S, Gaasterland T., Lazarowski E.R, Ross C.A, Yeo G.W, Sopher B.L, Magnuson G.K, Pinkerton A.B, Masliah E., La Spada A.R|
|Type of Article||Article|
|Keywords||activated receptor-delta; ad mouse models; deficits; diseases; expression; intranuclear inclusions; mitochondrial dysfunction; mutant huntingtin; neurodegenerative; reverse; synaptic plasticity; transgenic mice|
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.