Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport.
Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport.
复制标题
DOI：
10.1016/j.neuron.2017.03.027
复制
发表时间：
2017-04-05
期刊：
影响因子：
16.2
通讯作者：
Lagier-Tourenne C
中科院分区：
文献类型：
--
作者：
Gasset-Rosa F;Chillon-Marinas C;Goginashvili A;Atwal RS;Artates JW;Tabet R;Wheeler VC;Bang AG;Cleveland DW;Lagier-Tourenne C
包括亨廷顿氏病在内的神经退行性疾病的发病与年龄有很大关系。衰老细胞的特征包括核膜完整性受损，核细胞质运输受损，DNA双链断裂积累。我们发现突变的亨廷顿蛋白在小鼠皮层和纹状体中以剂量和年龄依赖的方式显著加速了所有这些细胞表型。亨廷顿蛋白连接的聚谷氨酰胺最初在细胞核中积累，导致核膜结构的破坏，核胞质运输必需因子（Gle1和RanGAP1）的部分隔离，以及mRNA的核内积累。在老年小鼠中，RanGAP1和聚谷氨酰胺的积累转移到核周和细胞质区域。与小鼠实验结果一致，在亨廷顿氏病患者的皮层中发现了核膜形态的明显改变、RanGAP1的异常定位和mRNA的核积累。总的来说，我们的研究结果确定了多聚谷氨酰胺依赖的核胞质运输抑制和核完整性改变是亨廷顿病的核心组成部分。
Onset of neurodegenerative disorders, including Huntington’s disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA. In aged mice, accumulation of RanGAP1 together with polyglutamine is shifted to perinuclear and cytoplasmic areas. Consistent with findings in mice, marked alterations in nuclear envelope morphology, abnormal localization of RanGAP1, and nuclear accumulation of mRNA were found in cortex of Huntington’s disease patients. Overall, our findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington’s disease.