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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia
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Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

机译：在多巴反应性肌张力障碍转基因模型中，基质体和基质多巴胺系统的差异参与

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Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinson's disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.
机译：多巴反应性肌张力障碍（DRD）是一种遗传性肌张力障碍，其特征是童年时期开始出现固定性肌张力障碍，并对左旋多巴的剂量相对较低产生了戏剧性且持续的反应。 DRD被认为是由于酪氨酸羟化酶（多巴胺的合成酶）的合成和活性降低，导致纹状体多巴胺缺乏所致。鉴于纹状体多巴胺缺乏是帕金森氏症的标志，DRD中肌张力障碍的起源机制对基底神经节运动控制模型提出了挑战。我们在这里报告DRD的转基因小鼠模型中的行为和解剖学观察，其中6-丙酮酰基-四氢蝶呤合酶的基因被靶向于呈现纹状体中TH合成的选择性功能障碍。突变小鼠表现出运动缺陷型，在表型上类似于人DRD的症状，并在纹状体中显示出TH标记的主要消耗，具有从前到后的明显梯度，导致尾部几乎完全丧失。令人惊讶的是，在纹状体中剩余的TH染色区域内，与周围基质相比，在脂质体中TH标记的损失更大。在出生后早期，运动症状首次出现时，质体中TH表达的主要丧失。我们认为，多巴胺丢失的不同的基质体-基质模式可能是确定DRD肌张力障碍的潜在机制的关键。

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