Rosiglitazone activation of PPAR gamma-dependent signaling is neuroprotective in mutant huntingtin expressing cells

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題名:	Rosiglitazone activation of PPAR gamma-dependent signaling is neuroprotective in mutant huntingtin expressing cells
作者:	Chiang, Ming-Chang Cheng, Yi-Chuan Nicol, Christopher J. Lin, Kuan-Hung Yen, Chia-Hui Chen, Shiang-Jiuun Huang, Rong-Nan
貢獻者:	生科所
關鍵詞:	Huntington's Disease Huntingtin PPAR gamma Rosiglitazone Neuroprotection PGC1 alpha
日期:	2015-11
上傳時間:	2016-02-26 13:17:57 (UTC+8)
摘要:	Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a crucial transcription factor for neuroprotection in several brain diseases. Using a mouse model of Huntington's Disease (HD), we recently showed that PPAR gamma not only played a major function in preventing HD, but also oral intake of a PPAR gamma agonist (thiazolidinedione, TZD) significantly reduced the formation of mutant Huntingtin (mHtt) aggregates in the brain (e.g., cortex and striatum). The molecular mechanisms by which PPAR gamma exerts its HD neuroprotective effects remain unresolved. We investigated whether the PPAR gamma agonist (rosiglitazone) mediates neuroprotection in the mHtt expressing neuroblastoma cell line (N2A). Here we show that rosiglitazone upregulated the endogenous expression of PPAR gamma, its downstream target genes (including PGCla, NRF-1 and Tfam) and mitochondrial function in mHtt expressing N2A cells. Rosiglitazone treatment also significantly reduced mHtt aggregates that included ubiquitin (Ub) and heat shock factor 1 (HSF1), as assessed by a filter-retardation assay, and increased the levels of the functional ubiquitinproteasome system (UPS), HSF1 and heat shock protein 27/70 (HSP27/70) in N2A cells. Moreover, rosiglitazone treatment normalized endoplasmic reticulum (ER) stress sensors Bip, CHOP and ASK1, and significantly increased N2A cell survival. Taken together, these findings unveil new insights into the mechanisms by which activation of PPAR gamma signaling protects against the HD-mediated neuronal impairment. Further, our data also support the concept that PPAR gamma may be a novel therapeutic target for treating HD. (C) 2015 Elsevier Inc. All rights reserved.
關聯:	EXPERIMENTAL CELL RESEARCH 卷: 338 期: 2 頁碼: 183-193
顯示於類別:	[生物科技研究所 ] 期刊論文

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