【摘要】：亨廷頓舞蹈癥(Huntington’s disease,HD)是一種常染色體顯性遺傳神經(jīng)退行性疾病,其典型特征為舞蹈樣不自主動(dòng)作和進(jìn)行性智能衰退,至今還沒有效治療手段。亨廷頓舞蹈癥致病基因?yàn)镮T15,其代謝產(chǎn)物命名為亨廷頓蛋白(Huntingtin,Htt),此疾病是由Htt氨基末端谷氨酰胺重復(fù)序列(poly glutamine,polyQ)過度延長導(dǎo)致的,這種polyQ過長的亨廷頓蛋白,在神經(jīng)細(xì)胞內(nèi)聚集、沉淀,可能是該病發(fā)病的關(guān)鍵,但是發(fā)病具體機(jī)制目前仍沒有得到闡明,所以,研究該疾病的致病機(jī)理對(duì)于藥物靶點(diǎn)的發(fā)現(xiàn)和疾病的治療具有十分重要的意義。本論文利用果蠅為模型,探究了銅離子影響亨廷頓舞蹈癥進(jìn)程的機(jī)理。我們發(fā)現(xiàn),在果蠅腦中調(diào)控銅離子轉(zhuǎn)運(yùn)蛋白的表達(dá)水平能夠顯著影響亨廷頓疾病的各種表型,調(diào)控膳食銅吸收的水平也F能夠一定程度影響亨廷頓疾病的進(jìn)程。進(jìn)一步研究表明,降低腦中銅含量能夠顯著降低毒性蛋白Htt-exon1 polyQ的寡聚體(oligomer)和多聚體(aggregate)水平,進(jìn)而延緩疾病進(jìn)程。突變Htt-exon1polyQ的兩個(gè)潛在的銅離子結(jié)合殘基Met8和His82后,蛋白毒性大大減小,而且不再受腦內(nèi)銅離子水平的調(diào)控。以上研究揭示,銅離子結(jié)合到亨廷頓蛋白上對(duì)于該蛋白的毒性發(fā)揮具有重要作用。簡而言之,我們的結(jié)果表明,HD承受了雙重水平的毒性:銅直接結(jié)合exon1促進(jìn)蛋白質(zhì)積聚以及銅非依賴性的polyQ毒性。這兩條平行的通路共同導(dǎo)致了Htt毒性,理想的HD治療應(yīng)該是將這些作用均考慮在內(nèi)的一種組合策略,該研究成果為亨廷頓藥物靶點(diǎn)的尋找和疾病治療提供了重要線索。
[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.
【學(xué)位授予單位】：清華大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R742.2

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