The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington’s disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood–brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

中文翻译：

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精氨酸是polyQ疾病模型的疾病改良剂，可稳定polyQ蛋白的构象。

聚谷氨酰胺（polyQ）疾病是一组遗传性神经退行性疾病，包括亨廷顿氏病，各种脊髓小脑性共济失调，脊髓和延髓性肌萎缩以及齿龈下睑板肌萎缩。它们是由每种疾病的致病基因中编码polyQ片段的CAG重复序列的异常扩增引起的。扩展的polyQ延伸区触发异常的β-sheet构象转变和低聚，然后在受影响的神经元中聚合polyQ蛋白，导致神经元毒性和神经变性。减轻polyQ疾病的症状和分子发病机理的疾病缓解疗法仍未满足临床需求。在这里，我们确定了精氨酸，一种化学分子伴侣，可促进适当的蛋白质折叠，通过稳定polyQ蛋白构象，靶向polyQ蛋白聚集上游过程的新型化合物。我们首先使用体外polyQ聚集测定，并确定精氨酸是有效的polyQ聚集抑制剂。我们的体外和细胞实验表明，精氨酸通过抑制有毒的β-sheet构象转变和polyQ蛋白的低聚，从而在形成不溶性聚集体之前发挥其抗聚集特性。精氨酸对神经症状和蛋白质聚集病理表现出治疗效果秀丽隐杆线虫，果蝇（Drosophila），以及两种不同的polyQ疾病小鼠模型。在症状发作后施用时，精氨酸在polyQ小鼠模型中也有效。由于精氨酸已被安全地用于尿素循环缺陷和线粒体肌病，脑病，乳酸和中风综合症患者，并有效地跨越了血脑屏障，因此精氨酸的药物替代方法将使其作为一种有希望的疾病而在临床上迅速应用。用于polyQ疾病的改良药物。