Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities
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DOI：
10.1016/j.nbd.2007.04.015
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发表时间：
2007-08-01
影响因子：
6.1
通讯作者：
Riess, O.
中科院分区：
文献类型：
--
作者：
Grundmann, K.;Reischmann, B.;Riess, O.
原发性扭转肌张力障碍是一种常染色体显性遗传性运动障碍。大多数病例是由编码 torsinA 的 DYT1 基因的框内删除 (GAG) 引起的。外显率和表型变异性的降低表明，torsinA 氨基酸序列的改变对于临床症状的发展是必要的，但还不够，并且其他因素必须促成疾病的实际表现。我们使用强鼠朊病毒蛋白启动子生成了 4 个独立的转基因小鼠品系，其中两个过表达人类突变型 torsinA 和两个过表达人类野生型 torsinA。我们的数据首次提供了体内证据，表明不仅突变型torsinA对神经元细胞有害，而且野生型torsinA在高水平过度表达时也会导致神经元功能障碍。这一假设得到 (i) 神经病理学发现、(ii) 神经化学、(iii) 行为异常和 (iv) DTI-MRI 分析的支持。 (c) 2007 Elsevier Inc. 保留所有权利。
Primary torsion dystonia is an autosomal-dominant inherited movement disorder. Most cases are caused by an in-frame deletion (GAG) of the DYT1 gene encoding torsinA. Reduced penetrance and phenotypic variability suggest that alteration of torsinA amino acid sequence is necessary but not sufficient for development of clinical symptoms and that additional factors must contribute to the factual manifestation of the disease. We generated 4 independent transgenic mouse lines, two overexpressing human mutant torsinA and two overexpressing human wildtype torsinA using a strong murine prion protein promoter. Our data provide for the first time in vivo evidence that not only mutant torsinA is detrimental to neuronal cells but that also wildtype torsinA can lead to neuronal dysfunction when overexpressed at high levels. This hypothesis is supported by (i) neuropathological findings, (ii) neurochemistry, (iii) behavioral abnormalities and (iv) DTI-MRI analysis. (c) 2007 Elsevier Inc. All rights reserved.