TORSIN AND THE NUCLEAR ENVELOPE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 扭转蛋白是存在于内质网/核膜（ER/NE）腔内的一个古老的保守AAA+蛋白家族。扭转蛋白A在NE中起作用，在NE中它与LAP 1（核纤层相关蛋白1）相互作用。DYT 1肌张力障碍是一种由框内缺失引起的神经发育疾病（插科打诨 E）在编码torsinA的基因中。虽然torsinA是普遍表达，DYT 1肌张力障碍是一种神经选择性疾病。因此，破译DYT 1肌张力障碍的分子事件不仅将产生合理治疗疾病所需的信息，而且还提供了以前未被认识到的正常神经元功能所需的过程的见解。DYT 1突变损害torsinA功能，小鼠中该功能的丧失导致神经元核膜的囊泡形成（NE“泡”）。TorsinA null（Tor 1a-/-）和疾病敲入（Tor 1aDE/DE）小鼠均表现出NE泡，其似乎是内核膜（INM）的外囊。像这种疾病一样，NE水泡是神经特异性的。LAP 1的过表达也导致NE水泡，连接LAP 1和torsinA功能。AAA+蛋白质修饰蛋白质底物，通常是解折叠蛋白质或分解蛋白质复合物。因此，我们假设Tor 1a突变小鼠的表型反映了AAA+蛋白（torsinA）作用于其底物（LAP 1）的失败。基于这些数据，我们认为，了解NE水泡发生的机制可能提供相关的疾病发病机制和torsinA功能的见解。本计画的目的是利用电子显微镜断层摄影术及免疫电子显微镜来确定NE泡是否起源于核孔。这个问题的发病机制的DYT 1肌张力障碍，并可能牵连torsinA功能的核孔的生物发生，这是知之甚少。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The torsins are an ancient family of well-conserved AAA+ proteins present within the endoplasmic reticular/nuclear envelope (ER/NE) lumen. TorsinA functions in the NE, where it interacts with LAP1 (lamina-associated protein 1). DYT1 dystonia is a neurodevelopmental disease caused by an in-frame deletion (gag; E) in the gene encoding torsinA. Although torsinA is ubiquitously expressed, DYT1 dystonia is a neural-selective disorder. Thus, deciphering the molecular events underlying DYT1 dystonia will not only yield information necessary for rational treatment of the disease, but also provide insight into previously unrecognized processes required for normal neuronal function. The DYT1 mutation impairs torsinA function, and loss of this function in mice causes vesiculation of neuronal nuclear envelope membranes (NE "blebs"). TorsinA null (Tor1a-/-) and disease knock-in (Tor1aDE/DE) mice both exhibit NE blebs, which appear to be outpouchings of the inner nuclear membrane (INM). Like the disease, NE blebs are neural-specific. Overexpression of LAP1 also causes NE blebs, linking LAP1 and torsinA function. AAA+ proteins modify protein substrates, typically unfolding proteins or disassembling protein complexes. Therefore, we hypothesize that the phenotype of Tor1a mutant mice reflects the failure of an AAA+ protein (torsinA) to act on its substrate (LAP1). Based on these data, we believe that understanding the mechanisms underlying NE bleb genesis may provide insight relevant to disease pathogenesis and torsinA function. The objective of this project is to use electron microscope (EM) tomography and immuno-electron microscopy to determine whether NE blebs originate from the nuclear pore. This question has implications for the pathogenesis of DYT1 dystonia and may implicate torsinA function in nuclear pore biogenesis, about which little is known.