title: 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.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Audrey S
authors.initials: AS
authors.lastname: Dickey
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Pineda
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Taiji
authors.initials: T
authors.lastname: Tsunemi
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.|Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.|Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Miranda
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Gilmore-Hall
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lomas
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Kunal R
authors.initials: KR
authors.lastname: Sampat
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Buttgereit
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Mark-Joseph Manalang
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: April L
authors.initials: AL
authors.lastname: Flores
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-7630-1403
authors.initials: M
authors.lastname: Arreola
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nicolas
authors.identifier: http://orcid.org/0000-0003-1038-192X
authors.initials: N
authors.lastname: Arbez
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Akimov
authors.affiliation: Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA.|Scripps Institute for Oceanography, University of California San Diego, La Jolla, California, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Gaasterland
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Lazarowski
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.|Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.|Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Gavin K
authors.initials: GK
authors.lastname: Magnuson
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California, USA.|Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.|Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.|Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.|Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA.|Department of Neurosciences, University of California San Diego, La Jolla, California, USA.|Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.|Rady Children's Hospital, San Diego, California, USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009068:Movement / Q000187:drug effects; D017072:Neostriatum / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C573927:4-(2,6-dimethyl-4-(4-trifluoromethoxyphenyl)piperazine-1-sulfonyl)indan-2-carboxylic acid; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D047494:PPAR delta; D010879:Piperazines; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides