Davies S W, Turmaine M, Cozens B A, Raza A S, Mahal A, Mangiarini L, Bates G P
Department of Anatomy and Developmental Biology, University College London, UK.
Philos Trans R Soc Lond B Biol Sci. 1999 Jun 29;354(1386):971-9. doi: 10.1098/rstb.1999.0448.
Huntington's disease (HD) is an inherited progressive neurodegenerative disease caused by the expansion of a polyglutamine repeat sequence within a novel protein. Recent work has shown that abnormal intranuclear inclusions of aggregated mutant protein within neurons is a characteristic feature shared by HD and several other diseases involving glutamine repeat expansion. This suggests that in each of the these disorders the affected nerve cells degenerate as a result of these abnormal inclusions. A transgenic mouse model of HD has been generated by introducing exon 1 of the HD gene containing a highly expanded CAG sequence into the mouse germline. These mice develop widespread neuronal intranuclear inclusions and neurodegeneration specifically within those areas of the brain known to degenerate in HD. We have investigated the sequence of pathological changes that occur after the formation of nuclear inclusions and that precede neuronal cell death in these cells. Although the relation between inclusion formation and neurodegeneration has recently been questioned, a full characterization of the pathways linking protein aggregation and cell death will resolve some of these controversies and will additionally provide new targets for potential therapies.
亨廷顿舞蹈症（HD）是一种由新发现的蛋白质中多聚谷氨酰胺重复序列扩展导致的遗传性进行性神经退行性疾病。最近的研究表明，神经元内异常的聚集突变蛋白核内包涵体是HD和其他几种涉及谷氨酰胺重复序列扩展的疾病共有的特征。这表明在这些疾病中，受影响的神经细胞因这些异常包涵体而退化。通过将含有高度扩展的CAG序列的HD基因外显子1导入小鼠种系，已构建出HD转基因小鼠模型。这些小鼠会出现广泛的神经元核内包涵体以及特异性地在HD中已知会退化的脑区发生神经退行性变。我们研究了在这些细胞中核内包涵体形成后、神经元细胞死亡前发生的病理变化顺序。尽管最近有人质疑包涵体形成与神经退行性变之间的关系，但全面描述连接蛋白质聚集和细胞死亡的途径将解决其中一些争议，并为潜在治疗提供新的靶点。
