Modeling pathogenesis of Huntington's disease with inducible neuroprogenitor cells.
Modeling pathogenesis of Huntington's disease with inducible neuroprogenitor cells.
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DOI：
10.1007/s10571-011-9679-0
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发表时间：
2011-07
影响因子：
4
通讯作者：
Wang, H.
中科院分区：
文献类型：
--
作者：
Dong, G.;Ferguson, J. M.;Duling, A. J.;Nicholas, R. G.;Zhang, D.;Rezvani, K.;Fang, S.;Monteiro, M. J.;Li, S.;Li, X-J.;Wang, H.
亨廷顿氏病（HD）是由编码聚谷氨酰胺（polyQ）的CAG三核苷酸重复序列在亨廷顿蛋白（htt）基因的第一外显子异常扩增引起的。尽管付出了巨大的努力，但亨廷顿舞蹈病（HD）的发病机制在很大程度上仍然不清楚，因为缺乏能够可靠地再现亨廷顿舞蹈病病理特征的模型。在这里，我们使用先前建立的四环素调节的大鼠神经祖细胞系HC2S2报道了HD的神经细胞模型。HC2S2细胞中标记htt外显子1（分别为28Q和74Q）的增强型绿色荧光蛋白（EGFP）的稳定表达不影响神经元的快速分化。然而，与表达野生型htt的细胞相比，表达突变型htt的细胞系表现出时间依赖性细胞死亡和神经性变性的增加，并且对氧化应激的易感性增加。在神经元老化过程中或细胞暴露于氧化应激试剂时，在表达74Q的细胞系中检测到蛋白质聚集增加，而在对应的细胞系中则没有检测到。这些结果表明，神经祖细胞系模拟HD的主要神经病理特征，可能为研究HD的神经发病机制和高通量筛选治疗化合物提供有用的工具。
Huntington’s disease (HD) is caused by an abnormal expansion of CAG trinucleotide repeats encoding polyglutamine (polyQ) in the first exon of the huntingtin (htt) gene. Despite considerable efforts, the pathogenesis of Huntington’s disease (HD) remains largely unclear due to a paucity of models that can reliably reproduce the pathological characteristics of HD. Here, we report a neuronal cell model of HD using the previously established tetracycline regulated rat neuroprogenitor cell line, HC2S2. Stable expression of enhanced green fluorescence protein (EGFP) tagged-htt exon 1 (referred to as 28Q and 74Q, respectively) in the HC2S2 cells did not affect rapid neuronal differentiation. However, compared to the cells expressing wild type htt, the cell line expressing mutant htt showed an increase in time-dependent cell death and neuritic degeneration, and displayed increased vulnerability to oxidative stress. Increased protein aggregation during the process of neuronal aging or when the cells were exposed to oxidative stress reagents was detected in the cell line expressing 74Q but not in its counterpart. These results suggest that the neuroprogenitor cell lines mimic the major neuropathological characteristics of HD and may provide a useful tool for studying the neuropathogenesis of HD and for high-throughput screening of therapeutic compounds.
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影响因子：
11.2
作者：
Seo, H;Sonntag, KC;Isacson, O
通讯作者：
Isacson, O
影响因子：
--
作者：
van Roon-Mom WM;Pepers BA;'t Hoen PA;Verwijmeren CA;den Dunnen JT;Dorsman JC;van Ommen GB
通讯作者：
van Ommen GB
影响因子：
4.7
作者：
Jeitner TM;Pinto JT;Krasnikov BF;Horswill M;Cooper AJ
通讯作者：
Cooper AJ
影响因子：
2.7
作者：
Walker, Francis O.
通讯作者：
Walker, Francis O.
DOI：
10.1073/pnas.93.4.1518
发表时间：
1996-02-20
影响因子：
11.1
作者：
Hoshimaru, M;Ray, J;Gage, FH
通讯作者：
Gage, FH