TorsinA influences GABA neuron migration and dopamine neuron development: Implic

描述(申请人提供)：这个项目的长期目标是了解DYT1基因的产物TorsinA如何调节发育中的大脑中的神经发生和神经元迁移。TorsinA是AAA+超家族蛋白质中的一员，通常介导蛋白质复合体的构象变化。大多数TorsinA定位于内质网和连接核膜的核膜，在那里它连接核膜和细胞骨架。在这个位置，TorsinA参与了细胞器的运动，包括分裂和迁移细胞中的核移位，这表明该蛋白在神经发生和神经元迁移中都发挥了作用。这里提出的实验将验证这样的假设，即TorsinA在GABA神经元迁移和大脑皮层和发育中的大脑基底节中多巴胺能系统的发育中发挥关键作用。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(又称DYT1肌张力障碍)的病理生理有关，DYT1基因的突变与DYT1基因的突变有关。实验将使用DYT1基因敲除小鼠和DYT1 delGAG敲入小鼠(后者代表DYT1肌张力障碍症基因)作为功能丧失或获得的模型。预计这些数据将在细胞和系统水平上为TorsinA在大脑发育中的作用提供深入的见解。了解Torsin A在中枢神经系统发育中的作用对于研究Torsin A的生物学功能与DYT1肌张力障碍的发病机制具有重要意义。疾病过程还没有与发育中的大脑中特定的细胞过程或分子机制联系在一起。因此，构建这种疾病的机制模型需要了解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所扮演的角色。公共卫生相关性：我们的研究与公共健康相关，因为它检查了与早发性扭转肌张力障碍(DYT1肌张力障碍)相关的基因突变可能损害大脑区域和控制运动的神经递质系统的发育的机制。

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.