Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States; Genetics Institute, University of Florida, Gainesville, FL, United States.
Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States.
Neurobiol Dis. 2021 Jul;154:105342. doi: 10.1016/j.nbd.2021.105342. Epub 2021 Mar 20.
Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, repetitive movement, and sometimes abnormal postures. DYT1 dystonia is one of the most common genetic dystonias, and most patients carry heterozygous DYT1 ∆GAG mutations causing a loss of a glutamic acid of the protein torsinA. Patients can be treated with anticholinergics, such as trihexyphenidyl, suggesting an abnormal cholinergic state. Early work on the cell-autonomous effects of Dyt1 deletion with ChI-specific Dyt1 conditional knockout mice (Dyt1 Ch1KO) revealed abnormal electrophysiological responses of striatal ChIs to muscarine and quinpirole, motor deficits, and no changes in the number or size of the ChIs. However, the Chat-cre line that was used to derive Dyt1 Ch1KO mice contained a neomycin cassette and was reported to have ectopic cre-mediated recombination. In this study, we generated a Dyt1 Ch2KO mouse line by removing the neomycin cassette in Dyt1 Ch1KO mice. The Dyt1 Ch2KO mice showed abnormal paw clenching behavior, motor coordination and balance deficits, impaired motor learning, reduced striatal choline acetyltransferase protein level, and a reduced number of striatal ChIs. Furthermore, the mutant striatal ChIs had a normal muscarinic inhibitory function, impaired quinpirole-mediated inhibition, and altered current density. Our findings demonstrate a cell-autonomous effect of Dyt1 deletion on the striatal ChIs and a critical role for the striatal ChIs and corticostriatal pathway in the pathogenesis of DYT1 dystonia.
肌张力障碍是一种以持续或间歇性肌肉收缩、重复运动和有时异常姿势为特征的神经运动障碍。DYT1 型肌张力障碍是最常见的遗传性肌张力障碍之一，大多数患者携带杂合性 DYT1 ∆GAG 突变，导致蛋白 torsinA 中的一个谷氨酸缺失。患者可以用抗胆碱能药物治疗，如三己芬迪，这表明存在异常的胆碱能状态。早期使用 ChI 特异性 Dyt1 条件性敲除小鼠（Dyt1 Ch1KO）进行 Dyt1 缺失的细胞自主效应研究表明，纹状体 ChIs 对毒蕈碱和喹吡罗的电生理反应异常、运动缺陷，以及 ChIs 的数量或大小没有变化。然而，用于衍生 Dyt1 Ch1KO 小鼠的 Chat-cre 系含有新霉素盒，并被报道存在异位 cre 介导的重组。在这项研究中，我们通过去除 Dyt1 Ch1KO 小鼠中的新霉素盒，生成了 Dyt1 Ch2KO 小鼠系。Dyt1 Ch2KO 小鼠表现出异常的爪紧握行为、运动协调和平衡缺陷、运动学习受损、纹状体胆碱乙酰转移酶蛋白水平降低以及纹状体 ChIs 数量减少。此外，突变纹状体 ChIs 具有正常的毒蕈碱抑制功能， quinpirole 介导的抑制受损，以及电流密度改变。我们的研究结果表明 Dyt1 缺失对纹状体 ChIs 具有细胞自主效应，纹状体 ChIs 和皮质纹状体通路在 DYT1 型肌张力障碍的发病机制中起着关键作用。
