Article

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

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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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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.)).

Author information

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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Albert R La Spada.

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