UBQLN2-蛋白酶通路在亨廷顿包涵体聚集及毒性中的作用及机制研究

Huntington's disease (HD) is an autosomal dominant polyglutamine neurodegenerative disease. The HTT gene is located on the short arm of chromosome 4, expansion of CAG in the HTT gene results in an abnormally long polyglutamine tract in the disease protein, which leads to protein misfolding, aggregation and gradually damages cells in the brain. Two main pathways are responsible for the clearance of misfolded proteins, the ubiquitin-proteasome pathway and the autophagy-lysosome system. Several lines of evidence suggest that UBQLN2 also functions in the ubiquitin-proteasome pathway to counter the accumulation and toxicity of polyglutamine diseases. Our previous works revealed that early recruitment of UBQLN2, ubiquitin and p62 to htt aggregates in human HD brain and HD knock-in mouse model. However, the exact functions and mechanisms of UBQLN2 are still under investigation. In the present study, we will determine whether UBQLN2 suppresses polyglutamine aggregation and toxicity, and further explore the underlying mechanisms. We will use cell line, primary neuron culture, and HD double transgenic mice （HD-KI/UBQLN2 overexpression and HD-KI/UBQLN2 knock-out mice) to test the hypothesis and our results will potentially provide a new drug target for HD disease.

亨廷顿病（Huntington’s disease，HD）是常染体显性遗传的多聚谷氨酰胺病，其致病基因位于4号染色体短臂，编码Huntingtin（Htt）蛋白，该基因5’编码区CAG拷贝异常增加导致突变Htt蛋白构象障碍，折叠异常，聚集在细胞核内形成包涵体，最终导致细胞损伤和死亡。细胞内存在泛素-蛋白酶小体和自噬溶酶体两条通路降解发生异常折叠的蛋白质，而UBQLN2是蛋白降解通路的重要成分。我们前期在亨廷顿病人脑标本及动物模型发现UBQLN2能早期和泛素（ubiquitin），p62共同征集入htt核内包涵体，但其具体功能尚不明确。本项目拟利用细胞系，原代培养神经元，双转基因小鼠：HD-KI/UBQLN2高表达小鼠和HD-KI/UBQLN2敲除小鼠模型，从分子-细胞-动物多层次揭示UBQLN2对HD包涵体聚集及毒性的影响及分子机制，为临床治疗亨廷顿病提供新的理论依据及潜在的治疗靶点。

亨廷顿病（Huntington’s disease， HD）是常染体显性遗传的多聚谷氨酰胺病，其致病基因位于4号染色体短臂，编码Huntingtin （Htt）蛋白，该基因5’编码区CAG拷贝异常增加导致突变Htt蛋白构象障碍，折叠异常，聚集在细胞核内形成包涵体，最终导致细胞损伤和死亡。细胞内存在泛素-蛋白酶小体和自噬溶酶体两条通路降解发生异常折叠的蛋白质，而UBQLN2是蛋白降解通路的重要成分。我们前期在亨廷顿病人脑标本及动物模型发现UBQLN2能早期和泛素（ubiquitin）, p62共同征集入htt核内包涵体，但其具体功能尚不明确。本项目利用细胞系，原代培养神经元，双转基因小鼠：HD-KI/UBQLN2敲除小鼠模型，从分子-细胞-动物多层次揭示UBQLN2对HD包涵体聚集及毒性的影响及分子机制，为临床治疗亨廷顿病提供新的理论依据及潜在的治疗靶点。

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