Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma

Ming Chang Chiang, Chiung Mei Chen, Maw Rong Lee, Hsiao Wen Chen, Hui Mei Chen, Yu Shuo Wu, Cheng Han Hung, Jheng Jie Kang, Ching Pang Chang, Chen Chang, Yih Ru Wu, Yau Sheng Tsai, Yijuang Chern

研究成果: Article同行評審

64 引文 斯高帕斯(Scopus)

摘要

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-g (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.

原文English
文章編號ddq322
頁(從 - 到)4043-4058
頁數16
期刊Human Molecular Genetics
19
發行號20
DOIs
出版狀態Published - 2010 七月 28

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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