Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (DeltaE) TorsinA in transgenic mice.
Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (DeltaE) TorsinA in transgenic mice.
复制标题
DOI：
10.1016/j.nbd.2010.04.016
复制
发表时间：
2010-09
影响因子：
6.1
通讯作者：
Ehrlich ME
中科院分区：
文献类型：
--
作者：
Page ME;Bao L;Andre P;Pelta-Heller J;Sluzas E;Gonzalez-Alegre P;Bogush A;Khan LE;Iacovitti L;Rice ME;Ehrlich ME
早发性扭转性肌张力障碍是一种常染色体显性遗传的可变型运动障碍，由编码蛋白torsinA的DYT 1中的谷氨酸（即ΔE）缺失引起。遗传和结构数据暗示肌张力障碍的基底神经节功能障碍。然而，TorsinA是弥散表达的，因此在泛神经元转基因小鼠模型中功能障碍的主要来源可能是模糊的。我们利用酪氨酸羟化酶（TH）启动子直接转基因表达特异性多巴胺能神经元的中脑，以确定细胞自主异常。通过微透析和快速循环伏安法检测到人野生型（hTorsinA）和突变型（ΔE-hTorsinA）蛋白的表达导致多巴胺释放的改变。在这些小鼠中检测到的运动异常模仿了在具有泛神经元转基因表达的转基因小鼠中观察到的运动异常。在TH-hTorsinA和TH-ΔE-hTorsinA中，面对相对于非转基因小鼠的异常细胞外DA水平，对可卡因的运动反应表明纹状体DA传递的补偿性突触后改变。这是第一个细胞亚型特异性DYT 1转基因小鼠，可以用于区分肌张力障碍的原发性和继发性变化，从而有助于靶向疾病治疗。
Early onset torsion dystonia is an autosomal dominant movement disorder of variable caused by a glutamic acid, i.e. ΔE, deletion in DYT1, encoding the protein torsinA. Genetic and structural data implicate basal ganglia dysfunction in dystonia. TorsinA, however, is diffusely expressed, and therefore the primary source of dysfunction may be obscured in pan-neuronal transgenic mouse models. We utilized the tyrosine hydroxylase (TH) promoter to direct transgene expression specifically to dopaminergic neurons of the midbrain to identify cell-autonomous abnormalities. Expression of both the human wild type (hTorsinA) and mutant (ΔE-hTorsinA) protein resulted in alterations of dopamine release as detected by microdialysis and fast cycle voltammetry. Motor abnormalities detected in these mice mimicked those noted in transgenic mice with pan-neuronal transgene expression. The locomotor response to cocaine in both TH-hTorsinA and TH-ΔE-hTorsinA, in the face of abnormal extracellular DA levels relative to non-transgenic mice, suggests compensatory, post-synaptic alterations in striatal DA transmission. This is the first cell-subtype-specific DYT1 transgenic mouse that can serve to differentiate between primary and secondary changes in dystonia, thereby helping to target disease therapies.