Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease
Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease
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DOI：
10.1038/nm985
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发表时间：
2004-02-01
期刊：
影响因子：
82.9
通讯作者：
Nukina, N
中科院分区：
文献类型：
--
作者：
Tanaka, M;Machida, Y;Nukina, N
抑制多聚谷氨酰胺诱导的蛋白质聚集可以为多聚谷氨酰胺疾病如亨廷顿病提供治疗选择。在这里，我们通过体外筛选研究表明，各种二糖可以抑制聚谷氨酰胺介导的蛋白质聚集。我们还发现，在亨廷顿病的细胞模型中，各种二糖减少了聚谷氨酰胺聚集体并增加了存活率。在亨廷顿病转基因小鼠模型中，口服海藻糖（这些二糖中最有效的一种）可减少大脑和肝脏中的聚谷氨酰胺聚集体，改善运动功能障碍并延长寿命。我们认为，这些有益的效果是海藻糖结合到扩展的聚谷氨酰胺和稳定的部分未折叠的含聚谷氨酰胺的蛋白质的结果。无毒性和高溶解度，加上口服给药的功效，使得海藻糖有希望作为治疗药物或用于治疗多聚谷氨酰胺疾病的先导化合物。因此，本文确定的糖-聚谷氨酰胺相互作用为聚谷氨酰胺疾病提供了一种新的治疗策略。
Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.