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


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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  1. 1

    Berger, J. & Moller, D.E. The mechanisms of action of PPARs. Annu. Rev. Med. 53, 409–435 (2002).

    CAS  PubMed  Google Scholar 

  2. 2

    Auboeuf, D. et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 46, 1319–1327 (1997).

    CAS  PubMed  Google Scholar 

  3. 3

    Kliewer, S.A. et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA 91, 7355–7359 (1994).

    CAS  PubMed  Google Scholar 

  4. 4

    Luquet, S. et al. Peroxisome proliferator-activated receptor–δ controls muscle development and oxidative capability. FASEB J. 17, 2299–2301 (2003).

    CAS  PubMed  Google Scholar 

  5. 5

    Schuler, M. et al. PGC1-α expression is controlled in skeletal muscles by PPAR-β, whose ablation results in fiber-type switching, obesity and type 2 diabetes. Cell Metab. 4, 407–414 (2006).

    CAS  PubMed  Google Scholar 

  6. 6

    Wang, Y.X. et al. Regulation of muscle fiber type and running endurance by PPAR-δ. PLoS Biol. 2, e294 (2004).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Narkar, V.A. et al. AMPK and PPAR-δ agonists are exercise mimetics. Cell 134, 405–415 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Girroir, E.E. et al. Quantitative expression patterns of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) protein in mice. Biochem. Biophys. Res. Commun. 371, 456–461 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Nance, M.A. Genetic testing of children at risk for Huntington’s disease. Neurology 49, 1048–1053 (1997).

    CAS  PubMed  Google Scholar 

  10. 10

    Ross, C.A. et al. Huntington’s disease and dentatorubral-pallidoluysian atrophy: proteins, pathogenesis and pathology. Brain Pathol. 7, 1003–1016 (1997).

    CAS  PubMed  Google Scholar 

  11. 11

    The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 (1993).

    Google Scholar 

  12. 12

    La Spada, A.R. & Taylor, J.P. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat. Rev. Genet. 11, 247–258 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Beal, M.F. et al. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci. 13, 4181–4192 (1993).

    CAS  PubMed  Google Scholar 

  14. 14

    Lin, M.T. & Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    CAS  PubMed  Google Scholar 

  15. 15

    Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M.E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    CAS  PubMed  Google Scholar 

  16. 16

    Riley, B.E. & Orr, H.T. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev. 20, 2183–2192 (2006).

    CAS  PubMed  Google Scholar 

  17. 17

    Cui, L. et al. Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127, 59–69 (2006).

    CAS  PubMed  Google Scholar 

  18. 18

    Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α–null mice. Cell 119, 121–135 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Weydt, P. et al. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1α in Huntington’s disease neurodegeneration. Cell Metab. 4, 349–362 (2006).

    CAS  PubMed  Google Scholar 

  20. 20

    Tsunemi, T. et al. PGC-1α rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra97 (2012).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Gray, M. et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci. 28, 6182–6195 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Chiang, M.C. et al. Modulation of energy deficiency in Huntington’s disease via activation of the peroxisome proliferator-activated receptor–γ. Hum. Mol. Genet. 19, 4043–4058 (2010).

    CAS  PubMed  Google Scholar 

  23. 23

    Jin, Y.N., Hwang, W.Y., Jo, C. & Johnson, G.V. Metabolic state determines sensitivity to cellular stress in Huntington disease: normalization by activation of PPAR-γ. PLoS One 7, e30406 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Quintanilla, R.A., Jin, Y.N., Fuenzalida, K., Bronfman, M. & Johnson, G.V. Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin–expressing cells: possible role of peroxisome proliferator-activated receptor–γ (PPAR-γ) in the pathogenesis of Huntington disease. J. Biol. Chem. 283, 25628–25637 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Bastie, C., Luquet, S., Holst, D., Jehl-Pietri, C. & Grimaldi, P.A. Alterations of peroxisome proliferator-activated receptor–δ activity affect fatty acid–controlled adipose differentiation. J. Biol. Chem. 275, 38768–38773 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Holst, D., Luquet, S., Kristiansen, K. & Grimaldi, P.A. Roles of peroxisome proliferator-activated receptors–δ and –γ in myoblast transdifferentiation. Exp. Cell Res. 288, 168–176 (2003).

    CAS  PubMed  Google Scholar 

  27. 27

    Peters, J.M. et al. Growth, adipose, brain and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor–β(δ). Mol. Cell. Biol. 20, 5119–5128 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23, 99–103 (1999).

    CAS  PubMed  Google Scholar 

  29. 29

    Guyenet, S.J. et al. A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J. Vis. Exp. 39, e1787 (2010).

    Google Scholar 

  30. 30

    Shirendeb, U.P. et al. Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Hum. Mol. Genet. 21, 406–420 (2012).

    CAS  PubMed  Google Scholar 

  31. 31

    Song, W. et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein 1 and increases its enzymatic activity. Nat. Med. 17, 377–382 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Dang, M.T. et al. Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc. Natl. Acad. Sci. USA 103, 15254–15259 (2006).

    CAS  PubMed  Google Scholar 

  33. 33

    Ferrante, R.J., Beal, M.F., Kowall, N.W., Richardson, E.P. Jr. & Martin, J.B. Sparing of acetylcholinesterase-containing striatal neurons in Huntington’s disease. Brain Res. 411, 162–166 (1987).

    CAS  PubMed  Google Scholar 

  34. 34

    Reiner, A. et al. Striatal parvalbuminergic neurons are lost in Huntington’s disease: implications for dystonia. Mov. Disord. 28, 1691–1699 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Hodges, A. et al. Regional and cellular gene expression changes in human Huntington’s disease brain. Hum. Mol. Genet. 15, 965–977 (2006).

    CAS  PubMed  Google Scholar 

  36. 36

    Willson, T.M., Brown, P.J., Sternbach, D.D. & Henke, B.R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527–550 (2000).

    CAS  PubMed  Google Scholar 

  37. 37

    Iwaisako, K. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor–δ agonist. Proc. Natl. Acad. Sci. USA 109, E1369–E1376 (2012).

    CAS  PubMed  Google Scholar 

  38. 38

    Schilling, G. et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8, 397–407 (1999).

    CAS  PubMed  Google Scholar 

  39. 39

    Landis, S.C. et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490, 187–191 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Perrin, S. Preclinical research: make mouse studies work. Nature 507, 423–425 (2014).

    PubMed  Google Scholar 

  41. 41

    Lu, M. et al. Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat. Med. 17, 618–622 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Chiang, M.C., Chern, Y. & Huang, R.N. PPAR-γ rescue of the mitochondrial dysfunction in Huntington’s disease. Neurobiol. Dis. 45, 322–328 (2012).

    CAS  PubMed  Google Scholar 

  43. 43

    Jin, J. et al. Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease. J. Neurochem. 125, 410–419 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Zheng, B. et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci. Transl. Med. 2, 52ra73 (2010).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Shin, J.H. et al. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell 144, 689–702 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Evans, R.M. & Mangelsdorf, D.J. Nuclear receptors, RXR, and the big bang. Cell 157, 255–266 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Cramer, P.E. et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Fitz, N.F., Cronican, A.A., Lefterov, I. & Koldamova, R. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.”. Science 340, 924 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Gines, S. et al. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum. Mol. Genet. 12, 497–508 (2003).

    CAS  PubMed  Google Scholar 

  50. 50

    Young, J.E., Martinez, R.A. & La Spada, A.R. Nutrient deprivation induces neuronal autophagy and implicates reduced insulin signaling in neuroprotective autophagy activation. J. Biol. Chem. 284, 2363–2373 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Young, J.E. et al. Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5 (Hrk). J. Neurosci. 29, 1987–1997 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Nithianantharajah, J., Barkus, C., Murphy, M. & Hannan, A.J. Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington’s disease transgenic mice. Neurobiol. Dis. 29, 490–504 (2008).

    CAS  PubMed  Google Scholar 

  53. 53

    Sopher, B.L. et al. Androgen receptor YAC–transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41, 687–699 (2004).

    CAS  PubMed  Google Scholar 

  54. 54

    Garden, G.A. et al. Polyglutamine-expanded ataxin-7 promotes non–cell-autonomous Purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J. Neurosci. 22, 4897–4905 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    La Spada, A.R. et al. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31, 913–927 (2001).

    CAS  PubMed  Google Scholar 

  56. 56

    Janssen, A.J. et al. Spectrophotometric assay for complex I of the respiratory chain in tissue samples and cultured fibroblasts. Clin. Chem. 53, 729–734 (2007).

    CAS  PubMed  Google Scholar 

  57. 57

    Aubry, L. et al. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid–lesioned rats. Proc. Natl. Acad. Sci. USA 105, 16707–16712 (2008).

    CAS  PubMed  Google Scholar 

  58. 58

    HD iPSC Consortium. Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat expansion–associated phenotypes. Cell Stem Cell 11, 264–278 (2012).

    Google Scholar 

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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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The authors declare no competing financial interests.

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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).

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