Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein
Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein
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DOI：
10.1006/exnr.1998.7005
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发表时间：
1999-03-01
影响因子：
5.3
通讯作者：
Mann, DMA
中科院分区：
文献类型：
--
作者：
Sieradzan, KA;Mechan, AO;Mann, DMA
核内包涵体是亨廷顿病（HD）及其转基因小鼠模型共同的病理特征。利用一组横跨整个亨廷顿蛋白分子的抗体，我们研究了HD患者额叶皮质和纹状体核内包涵体的免疫反应性模式，核内包涵体与抗泛素和抗亨廷顿蛋白N-末端部分的抗体反应（CAG 53 b，HP 1），但不与检测扩增的多聚谷氨酰胺束的HD 1和1C 2抗体，也不与更多的C-末端抗体。然而，1C 2，HP 1，CAG 53 b，和HD 1抗体检测到颗粒状细胞质沉积在皮质和纹状体神经元，也含有核内N-末端亨廷顿蛋白免疫反应，这些数据显示了一个差异的细胞内定位截断亨廷顿蛋白在HD脑。蛋白质片段的细胞质和细胞核聚集体都可能具有神经毒性。皮质核内包涵体的出现频率与CAG的大小、扩张程度相关，与发病年龄和死亡年龄呈负相关。纹状体没有检测到这种相关性，这很可能反映了死亡时累积的更高级的神经元损失，（C）1999年学术出版社。
Intranuclear inclusion bodies are a shared pathological feature of Huntington's disease (HD) and its transgenic mouse model. Using a panel of antibodies spanning the entire huntingtin molecule, we have investigated the pattern of immunoreactivity within the intranuclear inclusions in the frontal cortex and striatum of patients with HD, The intranuclear inclusions reacted with anti-ubiquitin and antibodies against the N-terminal portion of huntingtin (CAG53b, HP1), but not with HD1 and the 1C2 antibodies that detect the expanded polyglutamine tract nor the more C-terminal antibodies. However, the 1C2, HP1, CAG53b, and HD1 antibodies detected granular cytoplasmic deposits in cortical and striatal neurons that also contained intranuclear N-terminal huntingtin immunoreactivity, These data show a differential intracellular location of truncated huntingtin in the HD brain. Both the cytoplasmic and the nuclear aggregates of the protein fragments could be neurotoxic. The frequency of the cortical intranuclear inclusions correlated with the size of CAG; expansion and was inversely related to the age at onset and death. No such correlations were detected for the striatum, which most likely reflects a more advanced neuronal loss accrued by the time of death, (C) 1999 Academic Press.