title: Enhanced mitochondrial biogenesis ameliorates disease phenotype in a full-length mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a devastating illness and at present there is no disease modifying therapy or cure for it; and management of the disease is limited to a few treatment options for amelioration of symptoms. Recently, we showed that the administration of bezafibrate, a pan-PPAR agonist, increases the expression of PGC-1α and mitochondrial biogenesis, and improves phenotype and survival in R6/2 transgenic mouse model of HD. Since the R6/2 mice represent a 'truncated' huntingtin (Htt) mouse model of HD, we tested the efficacy of bezafibrate in a 'full-length' Htt mouse model, the BACHD mice. Bezafibrate treatment restored the impaired PPARγ, PPARδ, PGC-1α signaling pathway, enhanced mitochondrial biogenesis and improved antioxidant defense in the striatum of BACHD mice. Untreated BACHD mice show robust and progressive motor deficits, as well as late-onset and selective neuropathology in the striatum, which was markedly ameliorated in the BACHD mice treated with bezafibrate. Our data demonstrate the efficacy of bezafibrate in ameliorating both neuropathological features and disease phenotype in BACHD mice, and taken together with our previous studies with the R6/2 mice, highlight the strong therapeutic potential of bezafibrate for treatment of HD.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: White
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Shurubor
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior; Department of Psychiatry and Biobehavioral Sciences; and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA johri.ashu@gmail.com asj2002@med.cornell.edu abc2009@med.cornell.edu abchandra2010@gmail.com.
authors.forename: Ashu
authors.initials: A
authors.lastname: Johri
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000008:administration & dosage; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D001678:Organelle Biogenesis; D047494:PPAR delta / Q000096:biosynthesis* / Q000235:genetics; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D047494:PPAR delta; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D001629:Bezafibrate