title: Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease.
abstract: There is substantial evidence that impairment of peroxisome proliferator-activated receptor (PPAR)-γ-coactivator 1α (PGC-1α) levels and activity play an important role in Huntington's disease (HD) pathogenesis. We tested whether pharmacologic treatment with the pan-PPAR agonist bezafibrate would correct a deficiency of PGC-1α and exert beneficial effects in a transgenic mouse model of HD. We found that administration of bezafibrate in the diet restored levels of PGC-1α, PPARs and downstream genes to levels which occur in wild-type mice. There were significant improvements in phenotype and survival. In the striatum, astrogliosis and neuronal atrophy were attenuated and numbers of mitochondria were increased. Bezafibrate treatment prevented conversion of type I oxidative to type II glycolytic muscle fibers and increased the numbers of muscle mitochondria. Finally, bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice. These findings provide strong evidence that treatment with bezafibrate exerts neuroprotective effects which may be beneficial in the treatment of HD.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA. asj2002@med.cornell.edu
authors.forename: Ashu
authors.initials: A
authors.lastname: Johri
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hennessey
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Sharma
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wille
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D001629:Bezafibrate / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D005911:Gliosis / Q000473:pathology; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D018696:Neuroprotective Agents; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D001629:Bezafibrate
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