The role of nuclear envelope protein NET39 in skeletal muscle function and diseases

项目总结/摘要 核膜蛋白是维持核结构、基因表达和染色质的重要蛋白质 organization.核被膜蛋白和核纤层蛋白的突变导致许多人类疾病， 其中许多涉及骨骼肌缺陷，例如Emery-Dreifuss肌营养不良症（EDMD）。虽然 导致这些疾病的基因突变是已知的， 核被膜的扰动引起疾病仍然没有很好的理解。而且，目前还不清楚为什么 广泛表达的核膜蛋白的突变导致组织特异性发病机制， 横纹肌特异性缺陷我们的实验室最近表明，核膜跨膜蛋白39 （NET 39）是核膜结构和功能的肌肉特异性调节剂。NET 39在哺乳动物中下调。 EDMD患者肌肉活检，以及小鼠中Net 39的缺失导致核被膜变形，先天性 肌病和青少年致死率。在核膜内，NET 39与细胞膜的几种组分相互作用。 核被膜，如LEMD 2。我们对NET 39的研究提供了一个切入点，以解开长期存在的 为什么横纹肌在核膜相关疾病中特别受影响的难题。我们假设 NET 39在EDMD的发病机制中起关键的骨骼肌特异性作用。本项目的总体目标 NET 39的功能及其与其他核膜蛋白的相互作用， 包膜完整性和基因表达在骨骼肌稳态和疾病，并探讨作用 NET 39在EDMD和其他层粘连蛋白病中的作用。最终，我们希望利用这些见解来开发新的 EDMD和相关核纤层蛋白病的治疗策略。

Project Summary/Abstract Nuclear envelope proteins are essential for maintaining nuclear architecture, gene expression and chromatin organization. Mutations in nuclear envelope proteins and nuclear lamins cause numerous human diseases, many of which involve in skeletal muscle defects such as Emery-Dreifuss muscular dystrophy (EDMD). Although the genetic mutations responsible for these diseases are known, the molecular mechanisms whereby perturbations in the nuclear envelope cause disease are still not well understood. Moreover, it is still unclear why mutations in ubiquitously expressed nuclear envelope proteins lead to tissue-specific pathogenesis such as striated muscle-specific defects. Our lab recently showed that the nuclear envelope transmembrane protein 39 (NET39) is a muscle-specific regulator of nuclear envelope structure and function. NET39 is downregulated in EDMD patient muscle biopsies, and deletion of Net39 in mice caused nuclear envelope deformations, congenital myopathy and juvenile lethality. Within the nuclear envelope, NET39 interacts with several components of the nuclear envelope such as LEMD2. Our studies of NET39 provide an entry point to unravel the long-standing puzzle of why striated muscle is specifically affected in nuclear envelope related diseases. We hypothesize that NET39 plays a pivotal skeletal muscle-specific role in the pathogenesis of EDMD. The overall goals of this project are to define the functions of NET39 and its interactions with other nuclear envelope proteins in regulating nuclear envelope integrity and gene expression during skeletal muscle homeostasis and disease, and to explore the role of NET39 in EDMD and other laminopathies. Ultimately, we hope to use these insights to develop new therapeutic strategies for EDMD and related laminopathies.