Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease
Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease
复制标题
核和核外polyQ对亨廷顿病小鼠模型神经表型的贡献
DOI：
10.1093/hmg/ddi340
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发表时间：
2005-10-15
影响因子：
3.5
通讯作者：
Bates, GP
中科院分区：
文献类型：
--
作者：
Benn, CL;Landles, C;Bates, GP
在死后患有亨廷顿舞蹈病的大脑中，突变的 htt 存在于细胞核和细胞质区室中。为了剖析核和核外突变体 htt 对疾病发生和进展的影响，我们产生了一系列转基因小鼠品系，其中核定位或核输出信号序列已放置在携带 144 个谷氨酰胺的 htt 外显子 1 蛋白的 N 端。我们的数据表明外显子 1 突变蛋白作为寡聚或聚集复合物的一部分存在于细胞核中。增加细胞核中突变转蛋白的浓度足以并显着加速行为表型的发生和进展。此外，核外显子 1 突变蛋白足以诱导细胞质神经变性和转录失调。然而，我们的数据表明，细胞质突变外显子 1 htt（如果存在）会导致疾病进展。
In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggest that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.