TorsinA, TorsinB and Brain Development

该项目的长期目标是了解TorsinA在脑发育中的作用，并在TorsinA功能和早发性扭转肌张力障碍的发病机制之间建立联系。TorsinA是TOR1A基因的产物。 TOR1A基因突变会导致早发性扭转肌张力障碍，这是最常见的扭转肌张力障碍形式。Torsins是AAA+超家族蛋白质的成员，通常介导蛋白质复合体的构象变化。 TorsinA参与了包括神经元在内的多种细胞的膜转运和再循环。大脑发育在很大程度上依赖于膜的运输和回收。拟议的实验将检验TorsinA在中枢神经系统发育中扮演关键角色的假设。了解TorsinA在中枢神经系统发育中的作用对于 扭肌的生物学功能与早发性扭转肌张力障碍发病机制的相关性。这一疾病过程尚未与特定的细胞和分子机制联系在一起。因此，构建疾病的机制模型需要了解TorsinA在中枢神经系统中的作用。由于早发性扭转肌张力障碍的症状牵涉到基底节功能障碍和多巴胺能失衡，拟议的实验将集中在 基底节。实验将使用野生型和转基因小鼠，并将分两个阶段进行。首先，将使用蛋白质印迹和免疫组织化学方法检测TorsinA在胚胎和出生后早期大脑中的区域和细胞分布。这些研究的目标是了解这些蛋白质的表达是否在区域或细胞水平上受到发育调节。其次，表达突变型Toria基因或缺失TOR1A基因的转基因小鼠将作为功能丧失或获得的模型，以研究TOR1A在特定发育过程中的作用，如神经发生、神经元迁移、轴突生长和突触形成。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。这些数据与该计划中其他项目的数据结合在一起，对于将TorsinA的生物学功能与早发性扭转肌张力障碍的发病机制联系起来，以及开发这种疾病的机制模型和治疗范例将具有重要意义。

The long term goals of this project are to understand the role of torsinA in brain development and establish a link between torsinA function and the pathogenesis of early onset torsion dystonia. TorsinA is the product of TOR1A gene. Mutations in TOR1A cause early onset torsion dystonia, the most common form of torsion dystonia. Torsins are members of the AAA+ superfamily of proteins that typically mediate conformational changes in protein complexes. TorsinA is implicated in membrane trafficking and recycling in several cell types including neurons. Brain development relies critically on membrane trafficking and recycling events. The proposed experiments will test the hypothesis that torsinA plays critical roles in CNS development. Understanding the role of torsinA in CNS development is essential for correlating the biological functions of torsins with pathogenesis of early onset torsion dystonia. The disease process is not linked yet to specific cell and molecular mechanism. Therefore, constructing mechanistic models of the disease requires information on the role of torsinA in the CNS. Since the symptoms of early onset torsion dystonia implicate basal ganglia dysfunction and dopaminergic imbalance, the proposed experiments will focus on the development of the basal ganglia. The experiments will use wild type and transgenic mice, and will proceed in two stages. First, the regional and cellular distribution of torsinA will be examined in the embryonic and early postnatal brains using western blot and immunohistochemical methods. The goal of these studies is to understand if the expression of the proteins is developmentally regulated at regional or cellular levels. Second, transgenic mice that express mutant TORIA gene or that have deletions of the TOR1A gene will be used as loss or gain of function models to study the role of TOR1A in specific developmental processes such as neurogenesis, neuronal migration, axon growth and synaptogenesis. The data are expected to provide insights into the role of torsinA in brain development, at the cellular and systems level. The data when taken together with the data from the other projects in the program will be significant for linking the biological function of torsinA with the pathogenesis of early onset torsion dystonia and for developing mechanistic models and treatment paradigms for the disease.