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標題: Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma
作者: Chiang, M.C.
Chen, C.M.
Lee, M.R.
Chen, H.W.
Chen, H.M.
Wu, Y.S.
Hung, C.H.
Kang, J.J.
Chang, C.P.
Chang, C.
Wu, Y.R.
Tsai, Y.S.
Chern, Y.
關鍵字: ubiquitin-proteasome system;transgenic mouse model;central-nervous-system;urea cycle deficiency;expanded cag repeat;ppar-gamma;mutant huntingtin;insulin-resistance;adipose-tissue;neurodegenerative diseases
Project: Human Molecular Genetics
期刊/報告no:: Human Molecular Genetics, Volume 19, Issue 20, Page(s) 4043-4058.
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-gamma (PPAR gamma), 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 PPAR gamma seems to be a pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPAR gamma (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 PPAR gamma into HTT aggregates, chronic TZD treatment also elevated the availability of the PPAR gamma protein and subsequently normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPAR gamma coactivator-1 alpha genes). The protective effects described above appear to have been exerted, at least partially, via direct activation of PPAR gamma in the brain, as TZD was detected in the brains of mice treated with TZD and because a PPAR gamma agonist (rosiglitazone) protected striatal cells from mHTT-evoked energy deficiency and toxicity. We demonstrated that the systematic downregulation of PPAR gamma seems to play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPAR gamma is a potential therapeutic target for this disease.
ISSN: 0964-6906
DOI: 10.1093/hmg/ddq322
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