Shekhar Shashi, Vatsa Naman, Kumar Vipendra, Singh Brijesh Kumar, Jamal Imran, Sharma Ankit, Jana Nihar Ranjan
Hum Mol Genet. 2017 Jan 15;26(2):420-429. doi: 10.1093/hmg/ddw398.
Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain-penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan. Improvement of behavioural deficits are accompanied with the significant rescue of their progressively decreased body weight, brain weight and striatal volume. Interestingly, topotecan treatment also significantly reduced insoluble mutant huntingtin load in the HD mouse brain. Finally, we show that topotecan treatment to HD mouse not only inhibits the expression of transgenic mutant huntingtin, but also at the same time induces the expression of Ube3a, an ubiquitin ligase linked to the clearance of mutant huntingtin. These findings suggest that topotecan could be a potential therapeutic molecule to delay the progression of HD.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的进行性神经退行性疾病，由聚谷氨酰胺扩展突变型亨廷顿蛋白聚集形成包涵体所致，主要累及大脑。HD基因被发现后，尽管目前尚无有效治疗方法，但在理解该疾病发病机制方面已取得了显著进展，并且已确定了多个药物靶点。在此，我们证明，向HD转基因小鼠给予可穿透血脑屏障的拓扑异构酶1抑制剂拓扑替康进行治疗，可显著改善其运动行为异常，并显著延长其寿命。行为缺陷的改善伴随着其逐渐减轻的体重、脑重和纹状体体积的显著恢复。有趣的是，拓扑替康治疗还显著降低了HD小鼠脑中不可溶性突变型亨廷顿蛋白的负荷。最后，我们表明，对HD小鼠进行拓扑替康治疗不仅抑制了转基因突变型亨廷顿蛋白的表达，同时还诱导了与突变型亨廷顿蛋白清除相关的泛素连接酶Ube3a的表达。这些发现表明，拓扑替康可能是一种延缓HD病情进展的潜在治疗分子。
