Bhide P G, Day M, Sapp E, Schwarz C, Sheth A, Kim J, Young A B, Penney J, Golden J, Aronin N, DiFiglia M
Massachusetts General Hospital, Boston 02114, USA.
J Neurosci. 1996 Sep 1;16(17):5523-35. doi: 10.1523/JNEUROSCI.16-17-05523.1996.
Huntington's disease (HD) is caused by a genetic mutation that results in a polyglutamine expansion in huntingtin. The time course of neuronal loss in the HD striatum and other affected brain regions before the onset of symptoms is unknown. To determine the potential influence of huntingtin on brain development, we examined its expression in the developing mouse and in human control and HD brain. By Western blot, huntingtin was detected throughout the adult mouse brain and at all stages of embryonic and postnatal brain development. The protein increased significantly between postnatal day 7 (P7) and P15, which marks a period of active neuronal differentiation and enhanced sensitivity to excitotoxic injury in the rodent striatum. Immunoreactivity was found in neurons throughout the brain and localized mostly to the somatodendritic cytoplasm and to axons in fiber bundles. Staining was variable in different groups of neurons and within the same cell population. In developing brain, huntingtin was limited primarily to neuronal perikarya. Increased immunoreactivity in large neurons followed the gradient of neurogenesis and appeared in the basal forebrain and brainstem by embryonic days 15-17, in regions of cortex by P0-P1, and in the striatum by P7. In human brain at midgestation (19-21 weeks), huntingtin was detected in all regions. The brain of a 10-week-old infant with the expanded HD allele expressed a higher molecular weight mutant form of huntingtin at levels comparable to those of the wild-type protein. Thus, mutant huntingtin is expressed before neuronal maturation is complete. Results suggest that huntingtin has an important constitutive role in neurons during brain development, that heterogeneity in neuronal expression of the protein is developmentally regulated, and that the intraneuronal distribution of huntingtin increases in parallel with neuronal maturation. The presence of mutant huntingtin in the immature HD brain raises the possibility that neurons may be affected during brain development and possibly in the postnatal period when vulnerability to excitotoxic injury is at its peak.
亨廷顿舞蹈症（HD）由基因突变引起，该突变导致亨廷顿蛋白中多聚谷氨酰胺扩增。在症状出现之前，HD纹状体及其他受影响脑区神经元丧失的时间进程尚不清楚。为了确定亨廷顿蛋白对脑发育的潜在影响，我们检测了其在发育中的小鼠以及人类对照和HD大脑中的表达。通过蛋白质印迹法，在成年小鼠全脑中以及胚胎期和出生后脑发育的各个阶段均检测到亨廷顿蛋白。该蛋白在出生后第7天（P7）至P15之间显著增加，这标志着啮齿动物纹状体中神经元活跃分化以及对兴奋性毒性损伤敏感性增强的时期。在全脑神经元中均发现免疫反应性，且主要定位于体树突细胞质和纤维束中的轴突。不同神经元组以及同一细胞群体中的染色情况存在差异。在发育中的大脑中，亨廷顿蛋白主要局限于神经元胞体。大神经元中免疫反应性增加遵循神经发生梯度，在胚胎第15 - 17天出现在基底前脑和脑干，在出生后第0 - 1天出现在皮质区域，在出生后第7天出现在纹状体。在妊娠中期（19 - 21周）的人类大脑中，所有区域均检测到亨廷顿蛋白。一名携带扩增HD等位基因的10周龄婴儿的大脑中，表达了一种分子量更高的突变型亨廷顿蛋白，其水平与野生型蛋白相当。因此，突变型亨廷顿蛋白在神经元成熟完成之前就已表达。结果表明，亨廷顿蛋白在脑发育过程中对神经元具有重要的组成性作用，该蛋白在神经元中的表达异质性受发育调控，且亨廷顿蛋白在神经元内的分布与神经元成熟平行增加。未成熟HD大脑中存在突变型亨廷顿蛋白增加了神经元在脑发育期间以及可能在出生后对兴奋性毒性损伤易感性达到峰值时受到影响的可能性。
