Dysregulation of C/EBPα by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease
Dysregulation of C/EBPα by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease
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DOI：
10.1093/hmg/ddl481
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Chern, Yijuang
中科院分区：
文献类型：
--
作者：
Chiang, Ming-Chang;Chen, Hui-Mei;Chern, Yijuang
亨廷顿病（Huntington's disease，HD）是由亨廷顿蛋白（Huntingtin，Htt）基因CAG三核苷酸扩增引起的常染色体显性遗传性神经退行性疾病。使用两种HD小鼠模型，我们证明了以高氨血症、高血瓜氨酸和尿素循环酶抑制为特征的尿素循环缺陷是HD的显著特征。由此产生的氨毒性可能会加剧HD的神经功能缺损。C/EBP α是尿素循环酶转录的关键转录因子，其抑制似乎介导HD中的尿素循环缺陷。我们发现，在突变Htt的存在下，C/EBP α失去了与一个重要的辅因子（CREB结合蛋白）相互作用的能力。此外，突变体Htt将C/EBP α募集到聚集体中，以及抑制C/EBP α基因的表达。限制蛋白质饮食的消耗不仅导致C/EBP α活性的恢复，以及尿素循环缺陷和高氨血症的修复，而且还改善了Htt聚集体的形成，运动恶化，抑制纹状体脑源性神经营养因子和三种蛋白伴侣（Hsp 27，Hsp 70和Hsp 90）的正常化。旨在修复尿素循环缺陷的治疗可能为治疗HD提供新的策略。
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBP alpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBP alpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBP alpha into aggregates, as well as suppressed expression of the C/EBP alpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBP alpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.