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Abstract：
Huntington\'s disease is caused by an expansion of CAG repeats in exon 1 of the huntingtin gene encoding an extended PolyQ tract within the Huntingtin protein (mHtt). This expansion results in selective degeneration of striatal medium spiny projection neurons in the basal ganglia. The mutation causes abnormalities during neurodevelopment in human and mouse models. Here, we report that mHtt/PolyQ aggregates inhibit the cell cycle in the Drosophila brain during development. PolyQ aggregates disrupt the nuclear pore complexes of the cells preventing the translocation of cell cycle proteins such as Cyclin E, E2F and PCNA from cytoplasm to the nucleus, thus affecting cell cycle progression. PolyQ aggregates also disrupt the nuclear pore complex and nuclear import in mHtt expressing mammalian CAD neurons. PolyQ toxicity and cell cycle defects can be restored by enhancing RanGAP-mediated nuclear import, suggesting a potential therapeutic approach for this disease.
摘要：
亨廷顿病是由亨廷顿蛋白（mHtt）中编码延伸的PolyQ束的亨廷顿基因外显子1中CAG重复序列的扩展引起的。这种扩展导致基底神经节中纹状体中刺投射神经元的选择性变性。该突变在人类和小鼠模型的神经发育过程中引起异常。这里,我们报道mHtt/PolyQ聚集体在发育过程中抑制果蝇大脑中的细胞周期。PolyQ聚集体破坏细胞的核孔复合物，防止细胞周期蛋白如CyclinE，E2F和PCNA从细胞质到细胞核，从而影响细胞周期进程。PolyQ聚集体还破坏表达mHtt的哺乳动物CAD神经元中的核孔复合物和核输入。PolyQ毒性和细胞周期缺陷可以通过增强RanGAP介导的核导入来恢复，提示这种疾病的潜在治疗方法。
