Establishment of a molecular therapy for neurodegenerative diseases including the polyglutamine diseases.

多聚谷氨酰胺（polyQ）疾病是一类遗传性神经退行性疾病，包括亨廷顿病和脊髓小脑共济失调，其由疾病蛋白中polyQ片段的异常扩增引起。polyQ片段的扩增被认为通过构象转变赋予疾病蛋白毒性，导致致病性蛋白质-蛋白质相互作用，包括聚集体形成。我们之前鉴定了QBP 1，一种优先结合扩展的polyQ片段的肽，并且已经表明QBP 1在体外抑制polyQ蛋白聚集和在细胞模型中抑制细胞毒性。在这项研究中，1）我们表明，QBP 1的共表达抑制polyQ蛋白聚集和复眼变性，并挽救果蝇polyQ疾病模型中的过早死亡，表明QBP 1在体内预防polyQ诱导的神经变性。2)我们利用蛋白转导结构域（PTD）将QBP 1有效地递送到细胞中，并且表明PTD-QBP 1长期施用到polyQ疾病的小鼠模型的侧脑室中导致显著抑制施用部位周围的polyQ聚集。3)通过使用圆二色谱和电子显微镜的结构分析，我们证明QBP 1阻止扩展的polyQ蛋白经历毒性构象转变为富含β-折叠的结构，从而抑制淀粉样原纤维形成。我们的结论是，扩大polyQ蛋白的毒性构象转变是一个治疗靶点，QBP 1是一个潜在的治疗候选人，目前无法治疗的polyQ疾病。

The polyglutamine (polyQ) diseases are a class of inherited neurodegenerative diseases including Huntington s disease and the spinocerebellar ataxias, which are caused by abnormal expansions of the polyQ stretch within the disease proteins. Expansion of the polyQ stretch is thought to confer toxic properties on the disease proteins through a conformational transition, leading to pathogenic protein-protein interactions including aggregate formation. We previously identified QBP1, a peptide that preferentially binds the expanded polyQ stretch, and have shown that QBP1 inhibits polyQ protein aggregation in vitro and cytotoxicity in cellular models. In this study, 1) we show that co-expression of QBP1 suppresses polyQ protein aggregation and compound eye degeneration, and rescues premature death in Drosophila polyQ disease models, indicating that QBP1 prevents polyQ-induced neurodegeneration in vivo. 2) We utilized a protein transduction domain (PTD) to deliver QBP1 efficiently into cells, and show that long-term administration of PTD-QBP1 into the lateral ventricle of a mouse model of the polyQ diseases results in significant suppression of polyQ aggregation around the administration site. 3) By structural analysis using circular dichroism and electron microscopy, we demonstrate that QBP1 prevents the expanded polyQ protein from undergoing a toxic conformational transition to a β-sheet rich structure, resulting in inhibition of amyloid-like fibril formation. We conclude that the toxic conformational transition of the expanded polyQ protein is a therapeutic target, and QBP1 is a potential therapeutic candidate for the currently untreatable polyQ diseases.