TorsinA influences GABA neuron migration and dopamine neuron development: Implic

描述（由申请人提供）：该项目的长期目标是了解DYT1基因产物torsinA如何调节发育中大脑的神经发生和神经元迁移。TorsinA是AAA+超家族蛋白质的成员，其通常介导蛋白质复合物中的构象变化。大多数扭转蛋白A定位于内质网和邻接的核膜内，在那里它将核膜与细胞骨架连接。在这个位置，torsinA涉及细胞器的运动，包括核转位分裂和迁移细胞，这表明这种蛋白质在神经发生和神经元迁移的作用。这里提出的实验将测试的假设，torsinA在GABA神经元迁移和多巴胺能系统的发展中发挥关键作用的大脑皮层和基底神经节的发育大脑。这两个神经递质系统和大脑区域与早发性扭转肌张力障碍（也称为DYT1肌张力障碍）的病理生理学有关，这与DYT1基因突变有关。实验将使用DYT1敲除小鼠以及DYT1 delGAG敲入小鼠（后者代表DYT1肌张力障碍疾病基因型）作为功能丧失或获得模型。这些数据有望在细胞和系统水平上深入了解torsinA在大脑发育中的作用。了解torsinA在中枢神经系统发育中的作用对于将torsinA的生物学功能与DYT 1肌张力障碍（一种发育障碍）的发病机制相关联至关重要。疾病过程尚未与发育中的大脑中的特定细胞过程或分子机制联系起来。因此，构建该疾病的机制模型需要关于torsinA在发育中的大脑中的神经元迁移或神经元分化等过程中的作用的信息。公共卫生相关性：我们的研究与公共卫生有关，因为它研究了与早发性扭转肌张力障碍（DYT 1肌张力障碍）相关的基因突变可能损害运动控制的脑区和神经递质系统发育的机制。

DESCRIPTION (provided by applicant): The long term goals of this project are to understand how torsinA, the product of the DYT1 gene, regulates neurogenesis and neuronal migration in the developing brain. TorsinA is a member of the AAA+ superfamily of proteins that typically mediate conformational changes in protein complexes. The majority of TorsinA is localized within the endoplasmic reticulum and the contiguous nuclear envelope where it links the nuclear envelope with the cytoskeleton. In this location, torsinA is implicated in organelle movement, including nuclear translocation in dividing and migrating cells, suggesting a role for this protein in both neurogenesis and neuronal migration. The experiments proposed here will test the hypothesis that torsinA plays critical roles in GABA neuron migration and the development of the dopaminergic system in the cerebral cortex and basal ganglia of the developing brain. These two neurotransmitter systems and brain regions are implicated in the pathophysiology of early onset torsion dystonia (also called DYT1 dystonia), which is associated with mutations in the DYT1 gene. The experiments will use DYT1 knockout mice as well as DYT1 delGAG knock-in mice (the latter represent the DYT1 dystonia disease genotype) as loss or gain of function models. The data are expected to provide insights into the role of torsinA in brain development, at the cellular and systems level. Understanding the role of torsinA in CNS development is essential for correlating the biological functions of torsinA with pathogenesis of DYT1 dystonia, which is a developmental disorder. The disease process is not linked yet to specific cellular processes or molecular mechanisms in the developing brain. Therefore, constructing mechanistic models of the disease requires information on the role of torsinA in processes such as neuronal migration or neuronal differentiation in the developing brain. PUBLIC HEALTH RELEVANCE: Our research is relevant to public health because it examines the mechanisms by which the genetic mutation associated with the cause of early onset torsion dystonia (DYT1 dystonia) may impair development of brain regions and neurotransmitter systems underlying the control of movement.