PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease

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Title:	PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease
Authors:	Chiang, MC (Chiang, Ming-Chang) Chern, YJ (Chern, Yijuang) Huang, RN (Huang, Rong-Nan)
Contributors:	Grad Inst Biotechnol
Keywords:	Huntingtin Thiazolidinedione PPAR gamma PGC-1 alpha Mitochondrial function
Date:	2012-01
Issue Date:	2013-02-26 13:29:59 (UTC+8)
Abstract:	Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain (e.g., cortex and striatum), and causes devastating neuronal degeneration. Transcriptional dysfunction caused by mHtt is critical for HD. We recently demonstrated that a crucial transcription factor peroxisome proliferator-activated receptor-gamma (PPAR gamma) played a major function in the energy homeostasis observed in HD and that PPAR gamma is a potentially neuroprotective target for this disease. We report here that the transcript level of PPAR gamma was markedly downregulated in the cortex of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPAR gamma (thiazolidinedione, TZD) resulted in a beneficial effect on PPAR gamma. By reducing Htt aggregates and thereby ameliorating the recruitment of PPAR gamma into Htt aggregates, TZD treatment also elevated the availability of PPAR gamma level and subsequently normalized the expression of downstream genes (including PGC-1 alpha and several mitochondrial genes) in the cortex. The above protective effects appeared to be exerted by a direct activation of the PPAR gamma agonist (rosiglitazone) because rosiglitazone protected a neuroblastoma cell line (N2A) from mHtt-evoked mitochondrial deficiency. Our results reveal that TZD and rosiglitazone may play a protective role in HD, and support the view that PPAR gamma is a potential therapeutic target in HD. (C) 2011 Elsevier Inc. All rights reserved.
Relation:	NEUROBIOLOGY OF DISEASE 卷: 45 期: 1 頁數: 322-328
Appears in Collections:	[Graduate Institute of Biotechnology ] journal articles

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