以果蝇为模型研究铜对亨廷顿舞蹈症的影响机制

发布时间：2019-04-25 20:05

【摘要】：亨廷顿舞蹈症(Huntington’s disease,HD)是一种常染色体显性遗传神经退行性疾病,其典型特征为舞蹈样不自主动作和进行性智能衰退,至今还没有效治疗手段。亨廷顿舞蹈症致病基因为IT15,其代谢产物命名为亨廷顿蛋白(Huntingtin,Htt),此疾病是由Htt氨基末端谷氨酰胺重复序列(poly glutamine,polyQ)过度延长导致的,这种polyQ过长的亨廷顿蛋白,在神经细胞内聚集、沉淀,可能是该病发病的关键,但是发病具体机制目前仍没有得到阐明,所以,研究该疾病的致病机理对于药物靶点的发现和疾病的治疗具有十分重要的意义。本论文利用果蝇为模型,探究了铜离子影响亨廷顿舞蹈症进程的机理。我们发现,在果蝇脑中调控铜离子转运蛋白的表达水平能够显著影响亨廷顿疾病的各种表型,调控膳食铜吸收的水平也F能够一定程度影响亨廷顿疾病的进程。进一步研究表明,降低脑中铜含量能够显著降低毒性蛋白Htt-exon1 polyQ的寡聚体(oligomer)和多聚体(aggregate)水平,进而延缓疾病进程。突变Htt-exon1polyQ的两个潜在的铜离子结合残基Met8和His82后,蛋白毒性大大减小,而且不再受脑内铜离子水平的调控。以上研究揭示,铜离子结合到亨廷顿蛋白上对于该蛋白的毒性发挥具有重要作用。简而言之,我们的结果表明,HD承受了双重水平的毒性:铜直接结合exon1促进蛋白质积聚以及铜非依赖性的polyQ毒性。这两条平行的通路共同导致了Htt毒性,理想的HD治疗应该是将这些作用均考虑在内的一种组合策略,该研究成果为亨廷顿药物靶点的寻找和疾病治疗提供了重要线索。
[Abstract]:Huntington's disease (Huntington's disease,HD) is an autosomal dominant neurodegenerative disease characterized by dance-like involuntary movements and progressive decline of intelligence. So far there is no effective treatment. The cause of Huntington's disease is IT15, whose metabolite is named Huntington's protein (Huntingtin,Htt), which is caused by excessive prolongation of the Htt amino-terminal glutamine repeats (poly glutamine,polyQ), an overly long polyQ Huntington protein. Aggregation and precipitation in nerve cells may be the key to the pathogenesis of the disease, but the specific mechanism of the disease has not yet been clarified, so, The study of the pathogenesis of the disease is of great significance to the discovery of drug targets and the treatment of the disease. In this paper, the mechanism of copper ions affecting Huntington's disease was studied by using Drosophila melanogaster as a model. We found that regulating the expression of copper ion transporter in the brain of Drosophila melanogaster could significantly affect the phenotypes of Huntington disease, and the level of dietary copper uptake could also affect the progression of Huntington disease to a certain extent. Further studies showed that reducing the content of copper in the brain could significantly reduce the levels of oligomer (oligomer) and polymer (aggregate) of toxic protein Htt-exon1 polyQ, and then delay the progression of the disease. Two potential Cu ~ (2 +) binding residues Met8 and His82 of mutated Htt-exon1polyQ significantly reduced protein toxicity and were no longer regulated by the level of copper ions in the brain. These results suggest that copper ion binding to Huntington protein plays an important role in the toxicity of Huntington protein. In short, our results show that HD suffers from double levels of toxicity: direct copper binding to exon1 promotes protein accumulation and copper independent polyQ toxicity. These two parallel pathways lead to Htt toxicity, and ideal HD therapy should be a combination strategy that takes these effects into account. The results of this study provide an important clue for Huntington drug target search and disease therapy.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R742.2

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