Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out.
Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out.
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DOI：
10.1016/j.bbr.2012.02.029
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发表时间：
2012-05-01
影响因子：
2.7
通讯作者：
Li, Yuqing
中科院分区：
文献类型：
--
作者：
Yokoi, Fumiaki;Mai Tu Dang;Li, Yuqing
早发性全身扭转性肌张力障碍（肌张力障碍1）是一种遗传性运动障碍，由编码torsinA的DYT 1（TOR 1A）突变引起。大多数患者在DYT 1的一个等位基因中有3个碱基对缺失（ΔGAG），对应于蛋白质C末端区域中谷氨酸残基（ΔE）的缺失。基底神经节回路和小脑的功能改变已被报道在肌张力障碍。据报道，导致小脑功能改变的药理学操作或基因突变具有张力障碍症状，并已被用作表型啮齿动物模型。此外，异常小脑回路中的结构性病变，如小脑切除术，在这些模型中具有治疗作用。先前的一项研究表明，Dyt 1 ΔGAG杂合基因敲入（KI）小鼠在横梁行走试验中表现出运动缺陷。Dyt 1 ΔGAG杂合敲入（KI）和Dyt 1浦肯野细胞特异性敲除（Dyt 1 pKO）小鼠均表现出小脑浦肯野细胞的树突状改变。在此，Dyt 1 pKO小鼠在横梁行走试验中表现出显著更少的滑动次数，表明比对照同窝仔更好的运动性能和正常步态。此外，Dyt 1 ΔGAG KI/Dyt 1 pKO双突变小鼠表现出显著低于Dyt 1 ΔGAG杂合子KI小鼠的滑动次数，表明Purkinje细胞特异性敲除Dyt 1 ΔGAG杂合子KI小鼠中的Dyt 1野生型（WT）等位基因可挽救运动缺陷。这些结果表明，通过基因治疗或干预小脑浦肯野细胞下游的信号通路，浦肯野细胞中torsinA的分子病变可能会挽救肌张力障碍的运动症状1。
Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1.
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影响因子：
2.7
作者：
DeAndrade, Mark P.;Yokoi, Fumiaki;Li, Yuqing
通讯作者：
Li, Yuqing
DOI：
10.1073/pnas.0304375101
发表时间：
2004-01-20
影响因子：
11.1
作者：
Goodchild, RE;Dauer, WT
通讯作者：
Dauer, WT
影响因子：
9.9
作者：
Draganski, B;Thun-Hohenstein, C;May, A
通讯作者：
May, A
影响因子：
3.3
作者：
Fernagut, PO;Diguet, E;Tison, F
通讯作者：
Tison, F
影响因子：
5.3
作者：
Campbell, DB;North, JB;Hess, EJ
通讯作者：
Hess, EJ