Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA
Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA
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DOI：
10.1016/j.neures.2005.06.021
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发表时间：
2005-11-01
影响因子：
2.9
通讯作者：
Kanazawa, I
中科院分区：
文献类型：
--
作者：
Wang, YL;Liu, WZ;Kanazawa, I
亨廷顿病是一种常染色体显性遗传性神经退行性疾病，目前尚无有效的治疗方法。它是由相应蛋白质Huntingtin(HTT)中的多聚谷氨酰胺(Poly Q)区扩张引起的，因此抑制脑神经元中Huntingtin的表达有望延缓疾病的发生并减轻疾病的严重程度。在此，我们使用针对Huntingtin基因的小干扰RNA(SiRNAs)在HD小鼠模型R6/2中抑制转基因突变体Huntingtin的表达。结果表明，出生后早期脑室注射siRNAs抑制了脑神经元中转基因Huntingtin的表达，并导致纹状体神经元中核内包涵体的数量和大小减少。使用这种siRNA的治疗显著延长了模型鼠的寿命，改善了运动功能，并减缓了体重的下降。这项工作表明，基于siRNA的治疗有望成为HD的一种未来治疗方法。(C)2005年爱思唯尔爱尔兰有限公司和日本神经科学学会。版权所有。
Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD. (c) 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.