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PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically

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.

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Figure 1: Huntingtin and PPAR-δ physically interact.
Figure 2: PPAR-δ activation rescues transcriptional repression, mitochondrial membrane depolarization and neurotoxicity in HD neurons.
Figure 3: Interference with the transcriptional function of PPAR-δ yields neuron dysfunction and induces neurological phenotypes and mitochondrial abnormalities in transgenic mice.
Figure 4: Expression of dominant-negative PPAR-δ in neurons results in widespread neurodegeneration.
Figure 5: Expression of dominant-negative PPAR-δ in the striatum recapitulates HD-like motor dysfunction and transcriptional pathology.
Figure 6: Treatment with the PPAR-δ agonist KD3010 improves motor function, neurodegeneration and survival in HD mice, and KD3010 treatment rescues neurotoxicity in human HD neurons.

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Acknowledgements

We are grateful to S. Luquet (Université Paris Diderot) for the gift of the CAGGS-floxed-STOP-Ppard expression construct. ST-Hdh cells were a kind gift from M. MacDonald20,49 (Massachusetts General Hospital). BAC-HD97 mice21 were originally obtained from X.W. Yang (David Geffen School of Medicine at UCLA). This work was supported by funding from the Hereditary Disease Foundation, the Cure Huntington's Disease Initiative and grants from the US National Institutes of Health (R01 NS065874 (A.R.L.S.), R01 AG033082 (A.R.L.S.), National Research Service Award F32 NS081964 (A.S.D.) and P01 HL110873 (E.R.L.)).

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A.R.L.S. provided the conceptual framework for the study. A.S.D., V.V.P., T.T., B.L.S., E.R.L., G.W.Y., C.A.R., G.K.M., A.B.P., E.M. and A.R.L.S. designed the experiments. A.S.D., V.V.P., P.P.L., H.C.M., S.K.G.-H., N.L., K.R.S., A.B., M.-J.M.T., A.L.F., M.A., N.A., S.S.A., T.G., B.L.S., E.R.L., G.W.Y., E.M., G.K.M., A.B.P. and A.R.L.S. performed the experiments. A.S.D. and A.R.L.S. wrote the manuscript.

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Correspondence to Albert R La Spada.

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Dickey, A., Pineda, V., Tsunemi, T. et al. PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med 22, 37–45 (2016). https://doi.org/10.1038/nm.4003

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