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

聚谷氨酰胺（polyQ）病是包括亨廷顿病和脊髓小脑共济失调在内的一类遗传性神经退行性疾病，是由疾病蛋白内的聚q拉伸异常扩张引起的。polyQ拉伸的扩张被认为通过构象转变赋予疾病蛋白毒性，导致致病性蛋白-蛋白相互作用，包括聚集形成。我们之前发现了QBP1，一种优先结合扩大的polyQ拉伸的肽，并在体外和细胞模型中显示了QBP1抑制polyQ蛋白聚集和细胞毒性。在本研究中，1)我们发现QBP1的共表达抑制polyQ蛋白聚集和复眼变性，并挽救果蝇polyQ疾病模型的过早死亡，表明QBP1在体内阻止polyQ诱导的神经变性。2)我们利用蛋白转导结构域（PTD）将QBP1有效地传递到细胞中，并表明PTD-QBP1长期进入polyQ疾病小鼠模型的侧脑室可显著抑制给药部位周围的polyQ聚集。3)通过圆二色性和电子显微镜的结构分析，我们证明了QBP1可以阻止扩展的polyQ蛋白发生毒性构象转变，从而抑制淀粉样纤维的形成。我们得出结论，扩展的多q蛋白的毒性构象转变是一个治疗靶点，QBP1是目前无法治疗的多q疾病的潜在治疗候选者。

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.