학술논문
PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically
Document Type
Report
Author
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.
Source
Nature Medicine. January 1, 2016, p37, 11 p.
Subject
Language
English
ISSN
1078-8956
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.
The PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three subtypes--termed PPAR-α, PPAR-δ and PPAR-γ--serve as lipid sensors in response to increased energy requirements [...]
The PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three subtypes--termed PPAR-α, PPAR-δ and PPAR-γ--serve as lipid sensors in response to increased energy requirements [...]