Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells -: Possible role of peroxisome proliferator-activated receptor-γ (PPARγ) in the pathogenesis of Huntington disease
Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells -: Possible role of peroxisome proliferator-activated receptor-γ (PPARγ) in the pathogenesis of Huntington disease
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DOI：
10.1074/jbc.m804291200
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发表时间：
2008-09-12
影响因子：
4.8
通讯作者：
Johnson, Gail V. W.
中科院分区：
文献类型：
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作者：
Quintanilla, Rodrigo A.;Jin, Youngnam N.;Johnson, Gail V. W.
过氧化物酶体增殖物激活受体-γ(PPAR-γ)是PPAR转录因子家族的成员。合成的PPARγ激动剂被用作口服降血糖药物，用于治疗非胰岛素依赖型糖尿病。然而，新出现的证据表明，PPAR伽马激活剂也可以预防或减轻神经退行性变。鉴于这些先前的发现，本报告的重点是PPAR伽马激活在防止亨廷顿病(HD)线粒体功能丧失方面的潜在神经保护作用。在这些研究中，我们使用了在生理水平上表达野生型(STHdh(Q7/Q7))或突变型(STHdh(Q111/Q111))亨廷顿蛋白的纹状体细胞。突变型细胞经thapsigargin处理后，线粒体钙摄取显著降低，活性氧生成增加，线粒体膜电位显著降低。罗格列酮激活PPARγ可防止突变纹状体细胞受到病理性钙升高攻击时出现的线粒体功能障碍和氧化应激。罗格列酮的有益作用可能是通过激活PPARγ介导的，因为所有的保护作用都被PPARγ拮抗剂GW9662所阻止。此外，在突变的纹状体细胞中，PPARγ信号通路显著受损，PPARγ表达减少，PPARγ转录活性降低。罗格列酮治疗增加线粒体质量水平，提示PPAR伽马通路在纹状体细胞线粒体功能中起作用。综上所述，这些证据表明，罗格列酮激活PPARγ可以减轻表达亨廷顿蛋白的突变型纹状体细胞的线粒体功能障碍，这可能是改善HD患者线粒体功能障碍的重要治疗途径。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a member of the PPAR family of transcription factors. Synthetic PPAR gamma agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR gamma activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR gamma activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh(Q7/Q7)) or mutant (STHdh(Q111/Q111)) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR gamma activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR gamma, as all protective effects were prevented by the PPAR gamma antagonist GW9662. Additionally, the PPAR gamma signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR gamma expression and reduced PPAR gamma transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR gamma pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR gamma activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.