Enhanced mitochondrial biogenesis ameliorates disease phenotype in a full-length mouse model of Huntington's disease

• Published in: Human molecular genetics 2016-06, Vol.25 (11), p.2269-2282
• Main Authors: Chandra, Abhishek, Sharma, Abhijeet, Calingasan, Noel Y, White, Joshua M, Shurubor, Yevgeniya, Yang, X William, Beal, M Flint, Johri, Ashu
• Format: Article
• Language: English
• Subjects: Animals; Bezafibrate - administration & dosage; Corpus Striatum - drug effects; Corpus Striatum - pathology; Disease Models, Animal; Humans; Huntingtin Protein - genetics; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - pathology; Mice; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - genetics; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - antagonists & inhibitors; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - biosynthesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; PPAR delta - biosynthesis; PPAR delta - genetics; PPAR gamma - biosynthesis; PPAR gamma - genetics; Signal Transduction - drug effects
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw095

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.