Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults.
Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults.
复制标题
从亨廷顿基因中具有扩展的 CAG 重复序列的小鼠培养的新皮质神经元：对兴奋性毒素和其他损伤的脆弱性没有改变。
DOI：
10.1016/s0306-4522(03)00382-8
复制
发表时间：
2003
期刊：
影响因子：
3.3
通讯作者：
Choi,DW
中科院分区：
文献类型：
--
作者：
Snider,BJ;Moss,JL;Revilla,FJ;Lee,C-S;Wheeler,VC;Macdonald,ME;Choi,DW
谷氨酸介导的兴奋毒性可能有助于亨廷顿病和其他多谷氨酰胺重复疾病的发病机制。我们使用转基因和敲入小鼠的小鼠新皮质培养物来测试扩增的含聚谷氨酰胺的亨廷顿蛋白表达对神经元对兴奋毒素或其他损伤的易感性的影响。在小鼠Hdh基因外显子1表达正常长度（HdhQ20）或扩增（HdhQ111） CAG重复序列（敲入基因改变）的小鼠培养的神经元对n -甲基-d-天冬氨酸（NMDA）和盐酸盐介导的兴奋性毒性具有相似的易感性。这些神经元也表现出类似的氧化应激（暴露于10-100 μM百草枯或1 - 10 μM美萘醌24小时）、凋亡（暴露于30-100 nM斯桃孢素或1 μM马来酸二唑西林（MK-801） 48小时）和蛋白酶体抑制（暴露于0.3-3 μM MG-132 48小时）的易变性。在人类HD基因（Mangiarini et al., 1996， R6/2系）扩增CAG重复序列外显子1转基因小鼠（Mangiarini et al., 1996， R6/2系）中培养的新皮质神经元和非转基因的同居对照小鼠对NMDA和盐酸盐介导的兴奋性毒性也具有相似的易感性。这些观察结果表明，扩增的含聚谷氨酰胺的亨廷顿蛋白的表达不会急剧改变皮质神经元对兴奋毒性、氧化性或凋亡性损伤的易感性。
Glutamate-mediated excitotoxicity might contribute to the pathogenesis of Huntington's disease and other polyglutamine repeat disorders. We used murine neocortical cultures derived from transgenic and knock-in mice to test the effect of expression of expanded polyglutamine-containing huntingtin on neuronal vulnerability to excitotoxins or other insults. Neurons cultured from mice expressing either a normal length (HdhQ20) or expanded (HdhQ111) CAG repeat as a knock-in genetic alteration in exon one of the mouse Hdh gene [Hum Mol Genet 8 (1999) 115] had similar vulnerability to N-methyl-d-aspartate (NMDA) and kainate-mediated excitotoxicity. These neurons also exhibited similar vulnerability to oxidative stress (24 h exposure to 10–100 μM paraquat or 1–10 μM menadione), apoptosis (48 h exposure to 30–100 nM staurosporine or 1 μM dizocilpine maleate (MK-801) and proteasome inhibition (48 h exposure to 0.3–3 μM MG-132). Neocortical neurons cultured from mice transgenic for an expanded CAG repeat-containing exon 1 of the human HD gene (Mangiarini et al., 1996, R6/2 line) and non-transgenic littermate controls also had similar vulnerability to NMDA and kainate-mediated excitotoxicity. These observations suggest that expression of expanded polyglutamine-containing huntingtin does not acutely alter the vulnerability of cortical neurons to excitotoxic, oxidative or apoptotic insults.