Neuron——HTT损害细胞核的完整性和核质输出功能

HTT损害细胞核的完整性和核质输出功能

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.

1.扩增多聚htt能够以年龄和剂量依赖的方式损害核被膜的形态

2.扩增多聚htt损害核质输出mRNA

3.核多聚htt聚集物和核输出mRNA因子Gle1共定位

4.扩增htt聚集物能够富集RanGAP1

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