Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan.
Neurobiol Dis. 2012 Jan;45(1):322-8. doi: 10.1016/j.nbd.2011.08.016. Epub 2011 Aug 25.
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-γ (PPARγ) played a major function in the energy homeostasis observed in HD and that PPARγ is a potentially neuroprotective target for this disease. We report here that the transcript level of PPARγ was markedly downregulated in the cortex of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) resulted in a beneficial effect on PPARγ. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARγ into Htt aggregates, TZD treatment also elevated the availability of PPARγ level and subsequently normalized the expression of downstream genes (including PGC-1α and several mitochondrial genes) in the cortex. The above protective effects appeared to be exerted by a direct activation of the PPARγ 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 PPARγ is a potential therapeutic target in HD.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，由亨廷顿（Htt）基因中的 CAG 三核苷酸扩展引起。由此产生的突变亨廷顿蛋白（mHtt）在大脑中形成聚集体（例如皮质和纹状体），并导致毁灭性的神经元变性。mHtt 引起的转录功能障碍对 HD 至关重要。我们最近证明，关键转录因子过氧化物酶体增殖物激活受体-γ（PPARγ）在 HD 中观察到的能量平衡中发挥主要作用，并且 PPARγ 是这种疾病的潜在神经保护靶标。我们在这里报告说，HD 的转基因小鼠模型（R6/2）皮质中的 PPARγ 转录本水平明显下调。用 PPARγ 激动剂（噻唑烷二酮，TZD）治疗 R6/2 小鼠对 PPARγ 具有有益作用。通过减少 Htt 聚集体，从而改善 PPARγ 被募集到 Htt 聚集体中，TZD 治疗还提高了 PPARγ 水平的可用性，随后使皮质中的下游基因（包括 PGC-1α 和几种线粒体基因）的表达正常化。上述保护作用似乎是通过 PPARγ 激动剂（罗格列酮）的直接激活发挥的，因为罗格列酮可保护神经母细胞瘤细胞系（N2A）免受 mHtt 诱导的线粒体缺陷的影响。我们的结果表明，TZD 和罗格列酮可能在 HD 中发挥保护作用，并支持 PPARγ 是 HD 潜在治疗靶标的观点。
