Transgenic mouse model of early-onset DYT1 dystonia
Transgenic mouse model of early-onset DYT1 dystonia
复制标题
DOI：
10.1093/hmg/ddi012
复制
发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Olanow, CW
中科院分区：
文献类型：
--
作者：
Shashidharan, P;Sandu, D;Olanow, CW
早发性肌张力障碍是一种常染色体显性运动障碍，与torsinA中谷氨酸残基缺失相关。我们通过使用神经元特异性烯醇化酶启动子过表达人DeltaE-torsinA产生了四个独立系的转基因小鼠。早在出生后3周，转基因小鼠就出现了异常的不自主运动，表现为肌张力障碍，四肢自我夹紧。动物还表现出运动过度和快速双向盘旋。来自每个品系的大约40%的转基因小鼠表现出这些严重的行为异常。神经化学分析显示，受影响的转基因小鼠纹状体多巴胺减少，尽管在那些没有行为变化的小鼠中水平增加。免疫组化显示核周包涵体和聚集体染色阳性的泛素，torsinA和核纤层蛋白，标记的核膜。在脚桥核和其他脑干区域的神经元中检测到包涵体，其模式与DYT 1患者中描述的相似。这种转基因小鼠模型表现出与早发性肌张力障碍患者相似的行为和病理特征，可能有助于更好地了解这种疾病的病理生理学，并开发更有效的治疗方法。
Early-onset dystonia is an autosomal dominant movement disorder associated with deletion of a glutamic acid residue in torsinA. We generated four independent lines of transgenic mice by overexpressing human DeltaE-torsinA using a neuron specific enolase promoter. The transgenic mice developed abnormal involuntary movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks after birth. Animals also showed hyperkinesia and rapid bi-directional circling. Approximately 40% of transgenic mice from each line demonstrated these severe behavioral abnormalities. Neurochemical analyses revealed decreases in striatal dopamine in affected transgenic mice, although levels were increased in those that had no behavioral changes. Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA and lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to what has been described in DYT1 patients. This transgenic mouse model demonstrates behavioral and pathologic features similar to patients with early-onset dystonia and may help to better understand the pathophysiology of this disorder and to develop more effective therapies.