Nguyen Trent, Hamby Aaron, Massa Stephen M
Department of Neurology and Laboratory for Computational Neurochemistry and Drug Discovery, Veterans Administration Medical Center, University of California, San Francisco, CA 94121, USA.
Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11840-5. doi: 10.1073/pnas.0502177102. Epub 2005 Aug 8.
In investigating the role of metal ions in the pathogenesis of Huntington's disease, we examined the effects of clioquinol, a metal-binding compound currently in clinical trials for Alzheimer's disease treatment, on mutant huntingtin-expressing cells. We found that PC12 cells expressing polyglutamine-expanded huntingtin exon 1 accumulated less mutant protein and showed decreased cell death when treated with clioquinol. This effect was polyglutamine-length-specific and did not alter mRNA levels or protein degradation rates. Clioquinol treatment of transgenic Huntington's mice (R6/2) improved behavioral and pathologic phenotypes, including decreased huntingtin aggregate accumulation, decreased striatal atrophy, improved rotarod performance, reduction of weight loss, normalization of blood glucose and insulin levels, and extension of lifespan. Our results suggest that clioquinol is a candidate therapy for Huntington's disease and other polyglutamine-expansion diseases.
在研究金属离子在亨廷顿舞蹈病发病机制中的作用时，我们检测了氯碘羟喹（一种目前正处于治疗阿尔茨海默病临床试验阶段的金属结合化合物）对表达突变型亨廷顿蛋白的细胞的影响。我们发现，表达聚谷氨酰胺扩展的亨廷顿蛋白外显子1的PC12细胞在用氯碘羟喹处理后，积累的突变蛋白减少，细胞死亡也减少。这种效应具有聚谷氨酰胺长度特异性，且不改变mRNA水平或蛋白质降解速率。用氯碘羟喹治疗转基因亨廷顿舞蹈病小鼠（R6/2）可改善行为和病理表型，包括亨廷顿蛋白聚集体积累减少、纹状体萎缩减轻、转棒试验表现改善、体重减轻减少、血糖和胰岛素水平正常化以及寿命延长。我们的结果表明，氯碘羟喹是治疗亨廷顿舞蹈病和其他聚谷氨酰胺扩展疾病的候选疗法。
