Department of Neurology, College of Medicine,, College of Medicine, University of Florida, Gainesville, Florida, USA.
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, Florida, USA.
Mov Disord. 2016 Nov;31(11):1633-1639. doi: 10.1002/mds.26677. Epub 2016 May 31.
DYT1 dystonia is an autosomal-dominant movement disorder characterized by abnormal, often repetitive, movements and postures. Its hallmark feature is sustained or intermittent contractions of muscles involving co-contractions of antagonist muscle pairs. The symptoms are relieved with the anticholinergic drug trihexyphenidyl. The primary mutation is a trinucleotide deletion (ΔGAG) in DYT1/TOR1A, which codes for torsinA. Previous studies showed that (1) heterozygous Dyt1 ΔGAG knock-in mice, which have an analogous mutation in the endogenous gene, exhibit motor deficits and altered corticostriatal synaptic plasticity in the brain and (2) these deficits can be rescued by trihexyphenidyl. However, brain imaging studies suggest that the Dyt1 knock-in mouse models nonmanifesting mutation carriers of DYT1 dystonia. The aim of this work was to examine the hallmark features of DYT1 dystonia in the Dyt1 knock-in mice by analyzing muscular activities.
Wireless telemetry devices with biopotential channels were implanted to the bicep and the rectus femori muscles in Dyt1 knock-in mice, and muscular activities were recorded before and after trihexyphenidyl administration.
(1) Consistent with DYT1 dystonia patients, Dyt1 knock-in mice showed sustained contractions and co-contractions of the antagonistic bicep femoris and rectus femoris. (2) The abnormal muscle contractions were normalized by trihexyphenidyl.
The results suggest that the motor deficits in Dyt1 knock-in mice are likely produced by abnormal muscle contractions, and Dyt1 knock-in mice can potentially be used as a manifesting disease model to study pathophysiology and develop novel therapeutics. © 2016 International Parkinson and Movement Disorder Society.
DYT1 型肌张力障碍是一种常染色体显性遗传病，以异常、通常是重复性运动和姿势为特征。其标志性特征是涉及拮抗肌对的肌肉持续或间歇性收缩。其症状可用抗胆碱能药物三己芬迪缓解。主要突变是 DYT1/TOR1A 中的三核苷酸缺失（ΔGAG），该基因编码 torsinA。先前的研究表明：（1）具有内源性基因中类似突变的杂合 Dyt1 ΔGAG 敲入小鼠表现出运动缺陷和大脑皮质纹状体突触可塑性改变；（2）这些缺陷可以用三己芬迪挽救。然而，脑成像研究表明，Dyt1 敲入小鼠模型是非显性 DYT1 型肌张力障碍的突变携带者。本工作旨在通过分析肌肉活动来研究 Dyt1 敲入小鼠的 DYT1 型肌张力障碍的标志性特征。
在 Dyt1 敲入小鼠的肱二头肌和股直肌植入带有双电势通道的无线遥测装置，并在三己芬迪给药前后记录肌肉活动。
（1）与 DYT1 型肌张力障碍患者一致，Dyt1 敲入小鼠表现出拮抗的肱二头肌和股直肌的持续收缩和协同收缩。（2）三己芬迪可使异常肌肉收缩正常化。
结果表明，Dyt1 敲入小鼠的运动缺陷可能是由异常的肌肉收缩引起的，Dyt1 敲入小鼠可能被用作显性疾病模型，以研究病理生理学并开发新的治疗方法。 © 2016 国际帕金森和运动障碍学会。
