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

建立针对神经退行性疾病（包括多聚谷氨酰胺疾病）的分子疗法。

基本信息

批准号：
14570594
负责人：
NAGAI Yoshitaka
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570594/
关键词：
Gene Neuroscience Protein Neurological diseases Molecular therapy Neurodegenerative diseases Polyglutamine diseases Amyloid

项目摘要

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.

多聚谷氨酰胺(PolyQ)病是一类遗传性神经退行性疾病，包括亨廷顿S病和脊髓小脑性共济失调，是由疾病蛋白内多聚Q伸展异常扩张引起的。多聚Q延伸的扩展被认为通过构象转变赋予疾病蛋白质有毒性质，导致致病蛋白质-蛋白质相互作用，包括聚集形成。我们以前发现了QBP1，一种优先结合扩展的PolyQ伸展的多肽，并表明QBP1在体外抑制PolyQ蛋白的聚集，并在细胞模型中抑制细胞毒性。在本研究中，1)我们发现共表达QBP1抑制了多聚Q蛋白聚集和复眼变性，并挽救了果蝇多聚Q病模型的过早死亡，表明QBP1在体内阻止了多聚Q诱导的神经变性。2)我们利用蛋白转导结构域(PTD)将QBP1有效地运送到细胞内，并表明长期给予PTD-QBP1到多Q病小鼠模型的侧脑室可显著抑制给药部位周围的多Q聚集。3)通过圆二色谱和电子显微镜的结构分析，我们证明了QBP1阻止了扩展的PolyQ蛋白经历有毒的构象转变为富含β-Sheet的结构，从而抑制了淀粉样原纤维的形成。我们的结论是，扩展的多聚Q蛋白的毒性构象转变是一个治疗靶点，而QBP1是目前无法治疗的多聚Q疾病的潜在候选药物。