Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism
Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism
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DOI：
10.1016/j.bbr.2010.09.009
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发表时间：
2011-01-20
影响因子：
2.7
通讯作者：
Li, Yuqing
中科院分区：
文献类型：
--
作者：
DeAndrade, Mark P.;Yokoi, Fumiaki;Li, Yuqing
帕金森病（RDP）或DYT12型肌张力障碍是一种罕见的原发性全身性肌张力障碍。在生理应激源触发之前，患者不会出现任何症状。几天之内，患者就会同时表现出肌张力障碍和帕金森症。导致ATP1A3基因功能丧失的突变已被确定为RDP的原因。ATP1A3编码Ne+/K+- atp酶的α 3亚基，仅在神经元和心脏细胞中表达。我们之前已经创造了一种携带Atp1a3基因点突变的小鼠（人类Atp1a3基因的小鼠同源物），导致α 3亚基功能丧失。Atp1a3突变小鼠表现出甲基苯丙胺诱导的多动、空间学习和记忆缺陷以及运动增加。然而，在突变小鼠中，运动表型的全谱尚未被表征，并且尚不清楚约束应激等触发因素是否会影响运动表型。在这里，我们对正常杂合Atp1a3突变小鼠和暴露于约束应激的杂合Atp1a3突变小鼠的运动表型进行了表征。我们发现这种类型的触发在突变小鼠中引起运动协调和平衡的显著缺陷，这是其他基因型肌张力障碍小鼠模型的特征。此外，应激突变小鼠也有热敏感性降低和单胺代谢的改变。这些结果表明，Atp1a3突变小鼠模拟了RDP的几个特征，对该小鼠模型的进一步分析将为了解RDP的发病机制提供重要依据。(C) 2010 Elsevier B.V.版权所有
Rapid-onset dystonia with parkinsonism (RDP) or DYT12 dystonia is a rare form of primary, generalized dystonia. Patients do not present with any symptoms until triggered by a physiological stressor. Within days, patients will show both dystonia and parkinsonism. Mutations resulting in a loss of function in the ATP1A3 gene have been identified as the cause of RDP. ATP1A3 encodes the alpha 3 subunit of the Ne+/K+-ATPase, which is exclusively expressed in neurons and cardiac cells. We have previously created a line of mice harboring a point mutation of the Atp1a3 gene (mouse homolog of the human ATP1A3 gene) that results in a loss of function of the alpha 3 subunit. The Atp1a3 mutant mice showed hyperactivity, spatial learning and memory deficits, and increased locomotion induced by methamphetamine. However, the full spectrum of the motor phenotype has not been characterized in the mutant mice and it is not known whether triggers such as restraint stress affect the motor phenotype. Here, we characterized the motor phenotype in normal heterozygous Atp1a3 mutant mice and heterozygous Atp1a3 mutant mice that have been exposed to a restraint stress. We found that this type of trigger induced significant deficits in motor coordination and balance in the mutant mice, characteristic of other genotypic dystonia mouse models. Furthermore, stressed mutant mice also had a decreased thermal sensitivity and alterations in monoamine metabolism. These results suggest that the Atp1a3 mutant mouse models several characteristics of RDP and further analysis of this mouse model will provide great insight into pathogenesis of RDP. (C) 2010 Elsevier B.V. All rights reserved.