Thalamostriatal degeneration contributes to dystonia and cholinergic interneuron dysfunction in a mouse model of Huntington's disease
Thalamostriatal degeneration contributes to dystonia and cholinergic interneuron dysfunction in a mouse model of Huntington's disease
复制标题
DOI：
10.1186/s40478-020-0878-0
复制
发表时间：
2020-02-07
影响因子：
7.1
通讯作者：
Sadikot, Abbas F.
中科院分区：
文献类型：
--
作者：
Crevier-Sorbo, Gabriel;Rymar, Vladimir V.;Sadikot, Abbas F.
亨廷顿病 (HD) 是一种常染色体显性三核苷酸重复疾病，其特征为舞蹈样运动、肌张力障碍和纹状体神经元丢失。在多种细胞过程中，异常的神经递质信号传导和谷氨酸能皮质传入的营养支持减少是纹状体退化的主要机制。最近的研究表明丘脑纹状体（TS）系统是谷氨酸能输入的另一个主要来源，在 HD 中是异常的，尽管其表型意义尚不清楚。我们假设 TS 功能障碍在产生运动症状中发挥重要作用，并导致纹状体神经元亚型的退化。我们使用 HD 的 R6/2 小鼠模型的结果表明，束旁核 (PF) 的神经元（TS 传入的主要来源）在早期退化。在运动功能障碍或纹状体变性之前进行的 PF 损伤会导致肌张力障碍表型加速，并与胆碱能中间神经元的过早丧失相关。在 R6/2 小鼠中观察到的纹状体中型多棘神经元和小清蛋白阳性中间神经元的逐渐丧失并未因 PF 损伤而改变。使用线粒体免疫毒素的早期纹状体胆碱能消融提供了 R6/2 小鼠胆碱能对细胞能量衰竭的脆弱性增加的证据，并恶化了肌张力障碍表型。因此，在神经退行性应激存在的情况下，TS 系统有助于纹状体中间神经元亚型的营养支持，并且 TS 传入阻滞可能是导致 HD 发病机制的一种新的细胞非自主机制。此外，行为实验表明 TS 系统和纹状体胆碱能中间神经元是参与肌张力障碍发病机制的关键运动网络结构。这项工作表明，旨在挽救 TS 系统的治疗可能会保留纹状体结构和功能的重要元素，并缓解 HD 的症状。
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.