title: Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial transcription factor for neuroprotection in several brain diseases. Using a mouse model of Huntington's Disease (HD), we recently showed that PPARγ not only played a major function in preventing HD, but also oral intake of a PPARγ 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 PPARγ exerts its HD neuroprotective effects remain unresolved. We investigated whether the PPARγ agonist (rosiglitazone) mediates neuroprotection in the mHtt expressing neuroblastoma cell line (N2A). Here we show that rosiglitazone upregulated the endogenous expression of PPARγ, its downstream target genes (including PGC1α, 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 ubiquitin-proteasome 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 PPARγ signaling protects against the HD-mediated neuronal impairment. Further, our data also support the concept that PPARγ may be a novel therapeutic target for treating HD.
authors.affiliation: Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan. Electronic address: cmcphd@gmail.com.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Chang Gung University, Tao Yuan 333, Taiwan.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Cancer Biology and Genetics Division, Cancer Research Institute, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nicol
authors.affiliation: Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Department of International Business, Ming Chuan University, Taipei 111, Taiwan.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Yen
authors.affiliation: Department of Life Science and Institute of Ecology and Evolutionary Biology, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Shiang-Jiuun
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Department of Entomology and Research Center for Plant-Medicine, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Rong-Nan
authors.initials: RN
authors.lastname: Huang
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D014157:Transcription Factors; D025801:Ubiquitin; D000077154:Rosiglitazone; D046988:Proteasome Endopeptidase Complex
keywords: Huntingtin; Huntington's Disease; Neuroprotection; PGC1α; PPARγ; Rosiglitazone