Abstract：
Huntington\'s disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.
摘要：
亨廷顿病（HD）是一种神经退行性遗传疾病，由亨廷顿（HTT）基因的CAG重复序列扩展引起的行为，认知，和电机缺陷。目前对疾病发病机制的认识还不完全,并且没有临床使用改变疾病病程的干预措施。我们先前已经报道了HD的OVT73转基因绵羊模型的开发和表征。73聚谷氨酰胺重复序列在躯体上是稳定的，因此即使在5岁时也可能捕获疾病的前驱期，并且没有运动症状学，并且没有可检测的纹状体细胞损失。为了更好地了解疾病启动事件，我们对5岁的OVT73HD绵羊和年龄匹配的野生型对照进行了广泛研究队列的纹状体进行了单核转录组研究。我们已经确定了编码N-甲基-D-天冬氨酸（NMDA）的基因的转录上调，中等刺状神经元中的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和海藻酸盐受体，细胞类型优先在HD早期丢失。Further,我们观察到星形细胞谷氨酸摄取转运体和中等多刺神经元GABAA受体的上调，可以维持谷氨酸稳态。一起来看,这些观察结果支持谷氨酸兴奋性毒性假说,认为它是一种早期神经变性级联反应的启动过程,但毒性阈值可能受多种保护机制的调节.早期解决这种生化缺陷可以防止神经元损失并避免由细胞死亡引起的更复杂的继发性后果。
