Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
Hum Mol Genet. 2010 Oct 1;19(19):3702-20. doi: 10.1093/hmg/ddq285. Epub 2010 Jul 8.
The aggregation of mutant polyglutamine (polyQ) proteins has sparked interest in the role of protein quality-control pathways in Huntington's disease (HD) and related polyQ disorders. Employing a novel knock-in HD mouse model, we provide in vivo evidence of early, sustained alterations of autophagy in response to mutant huntingtin (mhtt). The HdhQ200 knock-in model, derived from the selective breeding of HdhQ150 knock-in mice, manifests an accelerated and more robust phenotype than the parent line. Heterozygous HdhQ200 mice accumulate htt aggregates as cytoplasmic aggregation foci (AF) as early as 9 weeks of age and striatal neuronal intranuclear inclusions (NIIs) by 20 weeks. By 40 weeks, striatal AF are perinuclear and immunoreactive for ubiquitin and the autophagosome marker LC3. Striatal NIIs accumulate earlier in HdhQ200 mice than in HdhQ150 mice. The earlier appearance of aggregate pathology in HdhQ200 mice is paralleled by earlier and more rapidly progressive motor deficits: progressive imbalance and decreased motor coordination by 50 weeks, gait deficits by 60 weeks and gross motor impairment by 80 weeks of age. At 80 weeks, heterozygous HdhQ200 mice exhibit striatal and cortical astrogliosis and a approximately 50% reduction in striatal dopamine receptor binding. Increased LC3-II protein expression, which is noted early and sustained throughout the disease course, is paralleled by increased expression of the autophagy-related protein, p62. Early and sustained expression of autophagy-related proteins in this genetically precise mouse model of HD suggests that the alteration of autophagic flux is an important and early component of the neuronal response to mhtt.
聚集体突变多聚谷氨酰胺（polyQ）蛋白激发了人们对蛋白质量控制通路在亨廷顿病（HD）和相关 polyQ 疾病中的作用的兴趣。利用新型亨廷顿病（HD）小鼠模型，我们提供了体内证据，证明突变亨廷顿蛋白（mhtt）会导致自噬的早期和持续改变。HdhQ200 基因敲入模型源自对 HdhQ150 基因敲入小鼠的选择性繁殖，其表现出比亲本系更快和更强的表型。杂合子 HdhQ200 小鼠早在 9 周龄时就会积累 htt 聚集体，形成细胞质聚集体焦点（AF），到 20 周时则会形成纹状体神经元核内包涵体（NII）。到 40 周时，纹状体 AF 位于核周，并对泛素和自噬体标记物 LC3 呈免疫反应性。HdhQ200 小鼠中的纹状体 NII 比 HdhQ150 小鼠更早积累。HdhQ200 小鼠中聚合体病理学更早出现，与之平行的是更早和更迅速的运动缺陷：50 周时出现进行性失衡和运动协调能力下降，60 周时出现步态缺陷，80 周时出现严重运动障碍。80 周时，杂合子 HdhQ200 小鼠表现出纹状体和皮质星形胶质细胞增生，以及纹状体多巴胺受体结合减少约 50%。LC3-II 蛋白表达的早期和持续增加，与自噬相关蛋白 p62 的表达增加相平行。在这个遗传精确的 HD 小鼠模型中，自噬相关蛋白的早期和持续表达表明自噬流的改变是神经元对 mhtt 反应的一个重要和早期组成部分。
