PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.
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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.
Disease Models, Animal
Gene Expression Profiling
In Vitro Techniques
Induced Pluripotent Stem Cells
Nerve Tissue Proteins
Real-Time Polymerase Chain Reaction
Receptors, Cytoplasmic and Nuclear
Published Version (Please cite this version)10.1038/nm.4003
Publication InfoAkimov, SS; Arbez, N; Arreola, M; Buttgereit, A; Dickey, Audrey S; Flores, AL; ... Yeo, GW (2016). PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med, 22(1). pp. 37-45. 10.1038/nm.4003. Retrieved from http://hdl.handle.net/10161/15677.
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Assistant Professor in Neurology
By incorporating different and novel approaches, my team is able to make connections not readily apparent and follow up with comprehensive experiments to thoroughly test the hypothesis. Basic molecular/cellular benchwork is vital to defining aspects of the problem and early testing of solutions, and I stress the translation of these results from bench to bedside. Broadly, my research is focused on determining how alterations in activity of a transcription factor can have wide-ranging do