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

Nature Medicine volume 22, pages 37–45 (2016)Cite this article

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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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Authors and Affiliations

  1. Department of Pediatrics, University of California San Diego, La Jolla, California, USA

    Audrey S Dickey, Taiji Tsunemi, Helen C Miranda, Stephen K Gilmore-Hall, Nicole Lomas, Kunal R Sampat, Anne Buttgereit, April L Flores, Martin Arreola & Albert R La Spada

  2. Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA

    Victor V Pineda, Mark-Joseph Manalang Torres & Bryce L Sopher

  3. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA

    Patrick P Liu, Gene W Yeo & Albert R La Spada

  4. Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA

    Patrick P Liu, Gene W Yeo & Albert R La Spada

  5. Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA

    Patrick P Liu, Terry Gaasterland, Gene W Yeo & Albert R La Spada

  6. Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicolas Arbez, Sergey S Akimov & Christopher A Ross

  7. Scripps Institute for Oceanography, University of California San Diego, La Jolla, California, USA

    Terry Gaasterland

  8. Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

    Eduardo R Lazarowski

  9. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Christopher A Ross

  10. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Christopher A Ross

  11. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Christopher A Ross

  12. Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA

    Gavin K Magnuson & Anthony B Pinkerton

  13. Department of Pathology, University of California San Diego, La Jolla, California, USA

    Eliezer Masliah

  14. Department of Neurosciences, University of California San Diego, La Jolla, California, USA

    Eliezer Masliah & Albert R La Spada

  15. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA

    Albert R La Spada

  16. Rady Children's Hospital, San Diego, California, USA

    Albert R La Spada

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  1. Audrey S Dickey
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Contributions

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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