Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease
Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease
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DOI：
10.1073/pnas.110078997
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Davies, SW
中科院分区：
文献类型：
--
作者：
Turmaine, M;Raza, A;Davies, SW
亨廷顿病（HD）是一种致命的遗传性神经退行性疾病，其特征在于人格改变、运动障碍和皮质下痴呆。HD是由扩增的多聚谷氨酰胺重复序列的表达引起的许多疾病之一。我们已经开发了几个品系的小鼠，它们是含有扩增CAG序列的HD基因外显子1的转基因小鼠。这些小鼠表现出明确的神经学表型，沿着神经元变化，这些变化是该疾病的特征性变化。我们以前曾观察到神经元核内包涵体的出现，但没有发现神经变性的证据。在这项研究中，我们报告说，这些小鼠的所有线路开发的迟发性神经退行性病变内的前扣带皮层，背侧纹状体，小脑的浦肯野神经元。死亡的神经元典型地表现出神经元核内内含物、细胞质和细胞核的浓缩以及质膜的皱褶，同时保持细胞器的超微结构保存。这些细胞不会出现细胞核或细胞质的起泡、凋亡小体或DNA片段化。神经元死亡发生在数周而不是数小时内。我们还发现，在死于HD的患者的大脑中，这些相同区域内的退化细胞具有相似的外观。因此，我们认为，神经元细胞死亡的机制在HD和转基因小鼠模型的HD既不是由凋亡，也不是由坏死。
Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by personality changes, motor impairment, and subcortical dementia. HD is one of a number of diseases caused by expression of an expanded polyglutamine repeat. We have developed several lines of mice that are transgenic for exon 1 of the HD gene containing an expanded CAG sequence. These mice exhibit a defined neurological phenotype along with neuronal changes that are pathognomonic for the disease. We have previously observed the appearance of neuronal intranuclear inclusions, but did not find evidence for neurodegeneration. In this study, we report that all lines of these mice develop a late onset neurodegeneration within the anterior cingulate cortex, dorsal striatum, and of the Purkinje neurons of the cerebellum. Dying neurons characteristically exhibit neuronal intranuclear inclusions, condensation of both the cytoplasm and nucleus, and ruffling of the plasma membrane while maintaining ultrastructural preservation of cellular organelles, These cells do not develop blebbing of the nucleus or cytoplasm, apoptotic bodies, or fragmentation of DNA. Neuronal death occurs over a period of weeks not hours. We also find degenerating cells of similar appearance within these same regions in brains of patients who had died with HD. We therefore suggest that the mechanism of neuronal cell death in both HD and a transgenic mouse model of HD is neither by apoptosis nor by necrosis.