Shashidharan P, Sandu D, Potla U, Armata I A, Walker R H, McNaught K S, Weisz D, Sreenath T, Brin M F, Olanow C W
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY 10029, USA.
Hum Mol Genet. 2005 Jan 1;14(1):125-33. doi: 10.1093/hmg/ddi012. Epub 2004 Nov 17.
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.
早发性肌张力障碍是一种常染色体显性运动障碍，与扭转蛋白A中谷氨酸残基的缺失有关。我们使用神经元特异性烯醇化酶启动子过表达人DeltaE-扭转蛋白A，生成了四个独立的转基因小鼠品系。这些转基因小鼠在出生后3周就出现了异常的不自主运动，表现为肌张力障碍样的肢体自扣。动物还表现出运动亢进和快速双向转圈。每个品系中约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水平降低，而没有行为变化的小鼠多巴胺水平升高。免疫组织化学显示核周包涵体和聚集体，它们对泛素、扭转蛋白A和核膜标记物核纤层蛋白呈阳性染色。在脚桥核神经元和其他脑干区域检测到包涵体，其模式与DYT1患者中所描述的相似。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，可能有助于更好地理解这种疾病的病理生理学，并开发更有效的治疗方法。
