Huntington's disease (HD) is an autosomal dominant trinucleotide repeat disorder characterized by choreiform movements, dystonia and striatal neuronal loss. Amongst multiple cellular processes, abnormal neurotransmitter signalling and decreased trophic support from glutamatergic cortical afferents are major mechanisms underlying striatal degeneration. Recent work suggests that the thalamostriatal (TS) system, another major source of glutamatergic input, is abnormal in HD although its phenotypical significance is unknown. We hypothesized that TS dysfunction plays an important role in generating motor symptoms and contributes to degeneration of striatal neuronal subtypes. Our results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage. PF lesions performed prior to motor dysfunction or striatal degeneration result in an accelerated dystonic phenotype and are associated with premature loss of cholinergic interneurons. The progressive loss of striatal medium spiny neurons and parvalbumin-positive interneurons observed in R6/2 mice is unaltered by PF lesions. Early striatal cholinergic ablation using a mitochondrial immunotoxin provides evidence for increased cholinergic vulnerability to cellular energy failure in R6/2 mice, and worsens the dystonic phenotype. The TS system therefore contributes to trophic support of striatal interneuron subtypes in the presence of neurodegenerative stress, and TS deafferentation may be a novel cell non-autonomous mechanism contributing to the pathogenesis of HD. Furthermore, behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia. This work suggests that treatments aimed at rescuing the TS system may preserve important elements of striatal structure and function and provide symptomatic relief in HD.

中文翻译：

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在亨廷顿舞蹈症的小鼠模型中，丘脑膜变性导致肌张力障碍和胆碱能中神经元功能障碍。

亨廷顿舞蹈病（HD）是一种常染色体显性遗传三核苷酸重复障碍，其特征是舞蹈样运动，肌张力障碍和纹状体神经元丢失。在多个细胞过程中，异常的神经递质信号和来自谷氨酸能皮质传入的营养支持减少是纹状体变性的主要机制。近期的研究表明，尽管谷胱甘肽表型的表型意义尚不清楚，但它是谷氨酸能输入的另一主要来源，其系统异常。我们假设TS功能障碍在产生运动症状中起重要作用，并有助于纹​​状体神经元亚型的变性。我们使用HD R6 / 2小鼠模型的结果表明，TS传入主要来源的束旁核（PF）的神经元在早期退化。在运动功能障碍或纹状体变性之前进行的PF病变导致加速性肌张力障碍表型，并与胆碱能中神经元的过早丧失有关。在PF病变中未改变在R6 / 2小鼠中观察到的纹状体中棘神经元和小白蛋白阳性中间神经元的进行性丧失。早期使用线粒体免疫毒素的纹状体胆碱能消融为增加R6 / 2小鼠胆碱能对细胞能量衰竭的脆弱性提供了证据，并加剧了肌张力障碍表型。因此，在存在神经退行性应激的情况下，TS系统有助于纹状体中间神经元亚型的营养支持，并且TS脱咖啡因作用可能是导致HD发病的新型细胞非自主机制。此外，行为实验表明，TS系统和纹状体胆碱能中间神经元是肌张力障碍发病机制中的关键运动网络结构。这项工作表明，旨在抢救TS系统的治疗方法可以保留纹状体结构和功能的重要元素，并提供HD的症状缓解。