Sathasivam K, Hobbs C, Mangiarini L, Mahal A, Turmaine M, Doherty P, Davies S W, Bates G P
GKT Medical and Dental School, King's College, Guy's Hospital, London, UK.
Philos Trans R Soc Lond B Biol Sci. 1999 Jun 29;354(1386):963-9. doi: 10.1098/rstb.1999.0447.
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. A mouse model of this disease has been generated by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line (R6 lines). Transgenic mice develop a progressive neurological phenotype with a movement disorder and weight loss similar to that in HD. We have previously identified neuronal inclusions in the brains of these mice that have subsequently been established as the pathological hallmark of polyglutamine disease. Inclusions are present before symptoms, which in turn occur long before any selective neuronal cell death can be identified. We have extended the search for inclusions to skeletal muscle, which, like brain, contains terminally differentiated cells. We have conducted an investigation into the skeletal muscle atrophy that occurs in the R6 lines, (i) to provide possible insights into the muscle bulk loss observed in HD patients, and (ii) to conduct a parallel analysis into the consequence of inclusion formation to that being performed in brain. The identification of inclusions in skeletal muscle might be additionally useful in monitoring the ability of drugs to prevent inclusion formation in vivo.
亨廷顿舞蹈症（HD）是一种由CAG多聚谷氨酰胺重复序列扩增引起的遗传性神经退行性疾病。通过将携带高度扩增CAG重复序列的人类HD基因外显子1导入小鼠生殖系（R6系），已建立了该疾病的小鼠模型。转基因小鼠会出现进行性神经表型，伴有运动障碍和体重减轻，类似于HD患者。我们之前在这些小鼠的大脑中发现了神经元内含物，这些内含物随后被确认为多聚谷氨酰胺疾病的病理标志。内含物在症状出现之前就已存在，而症状又远在任何选择性神经元细胞死亡被识别之前就已出现。我们将对内含物的搜索扩展到骨骼肌，骨骼肌与大脑一样，含有终末分化细胞。我们对R6系小鼠出现的骨骼肌萎缩进行了研究，（i）以便为HD患者中观察到的肌肉量减少提供可能的见解，（ii）并对内含物形成的后果进行与在大脑中进行的分析相平行的分析。在骨骼肌中鉴定内含物可能在监测药物在体内预防内含物形成的能力方面也很有用。
