FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease
FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease
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DOI：
10.1093/hmg/ddt615
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发表时间：
2014-05-01
影响因子：
3.5
通讯作者：
Maglione, Vittorio
中科院分区：
文献类型：
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作者：
Di Pardo, Alba;Amico, Enrico;Maglione, Vittorio
亨廷顿病 (HD) 是一种遗传性神经退行性疾病，目前无法治愈，也没有办法阻止甚至减缓其引起的大脑变化。在本研究中，我们旨在调查FTY720（第一个被批准的多发性硬化症口服疗法）是否可能对HD模型有效，并最终构成治疗该疾病的替代治疗方法。在这里，我们利用临床前靶点验证范例并检查了 R6/2 HD 小鼠模型中长期施用 FTY720 的体内功效。我们的研究结果表明，FTY720 改善了 R6/2 小鼠的运动功能、延长了生存期并减少了脑萎缩。 FTY720 给药的有益效果与神经元活性和连接性的显着增强以及突变亨廷顿蛋白聚集体的减少有关，同时还与突变亨廷顿蛋白在丝氨酸 13/16 残基处的磷酸化增加有关，预计这会减弱蛋白质毒性。
Huntington disease (HD) is a genetic neurodegenerative disorder for which there is currently no cure and no way to stop or even slow the brain changes it causes. In the present study, we aimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may be effective in HD models and eventually constitute an alternative therapeutic approach for the treatment of the disease. Here, we utilized preclinical target validation paradigms and examined the in vivo efficacy of chronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improved motor function, prolonged survival and reduced brain atrophy in R6/2 mice. The beneficial effect of FTY720 administration was associated with a significant strengthening of neuronal activity and connectivity and, with reduction of mutant huntingtin aggregates, and it was also paralleled by increased phosphorylation of mutant huntingtin at serine 13/16 residues that are predicted to attenuate protein toxicity.