title: Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma.
abstract: Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. Here, we report that the transcript of the peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor that is critical for energy homeostasis, was markedly downregulated in multiple tissues of a mouse model (R6/2) of HD and in lymphocytes of HD patients. Therefore, downregulation of PPARγ seems to be a pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, formation of mutant Htt aggregates, jeopardized global ubiquitination profiles, reduced expression of two neuroprotective proteins (brain-derived neurotrophic factor and Bcl-2) and shortened life span exhibited by these mice. By reducing HTT aggregates and, thus, ameliorating the recruitment of PPARγ into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARγ protein and subsequently normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPARγ coactivator-1 alpha genes). The protective effects described above appear to have been exerted, at least partially, via direct activation of PPARγ in the brain, as TZD was detected in the brains of mice treated with TZD and because a PPARγ agonist (rosiglitazone) protected striatal cells from mHTT-evoked energy deficiency and toxicity. We demonstrated that the systematic downregulation of PPARγ seems to play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARγ is a potential therapeutic target for this disease.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Maw-Rong
authors.initials: MR
authors.lastname: Lee
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Yu-Shuo
authors.initials: YS
authors.lastname: Wu
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Hung
authors.forename: Jheng-Jie
authors.initials: JJ
authors.lastname: Kang
authors.forename: Ching-Pang
authors.initials: CP
authors.lastname: Chang
authors.forename: Chen
authors.initials: C
authors.lastname: Chang
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D015536:Down-Regulation; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors
chemical_list: D051275:Glucose Transporter Type 4; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione