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      Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells.

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          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.

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          Author and article information

          Exp. Cell Res.
          Experimental cell research
          Elsevier BV
          Nov 01 2015
          : 338
          : 2
          [1 ] Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan. Electronic address: cmcphd@gmail.com.
          [2 ] Department of Biochemistry and Molecular Biology, Chang Gung University, Tao Yuan 333, Taiwan.
          [3 ] 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.
          [4 ] Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan.
          [5 ] Department of International Business, Ming Chuan University, Taipei 111, Taiwan.
          [6 ] Department of Life Science and Institute of Ecology and Evolutionary Biology, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
          [7 ] Department of Entomology and Research Center for Plant-Medicine, National Taiwan University, Taipei 106, Taiwan.

          Huntingtin,Huntington's Disease,Neuroprotection,PGC1α,PPARγ,Rosiglitazone


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