Molecular Mechanisms of Schwann Cell Myelination

描述(申请人提供)：髓鞘围绕着许多轴突。 中枢和外周神经系统，在那里它促进快速 神经冲动的传导，并提供一种外在的营养效应 促进轴突成熟和存活。髓鞘功能障碍和脱髓鞘 这是导致人类神经功能障碍的主要原因，可能是致命的。 从历史上看，这些原发性髓鞘疾病的神经缺陷是 被认为是髓鞘病理的结果。然而，最近的研究表明 在一些原发髓鞘疾病中发现了轴突变性。最多的 人类遗传性髓鞘病的常见原因是基因复制 改变髓鞘蛋白的剂量。关于蜂窝细胞的许多已知情况 以及正常髓鞘形成和遗传性骨髓炎发病机制的分子方面 髓鞘疾病是从对啮齿动物的研究中获得的，在这些啮齿动物中，髓鞘 蛋白质基因发生突变、缺失或过度表达。我们已经开发出 过表达P0的PNS和CNS髓鞘异常转基因小鼠模型 蛋白，雪旺细胞中PNS髓磷脂的主要结构蛋白，并通过 髓鞘少突胶质细胞高水平表达P0蛋白。这个 本应用程序的总体目标是了解P0过度表达是如何导致 髓鞘和轴突病理。过表达P0蛋白包膜的雪旺细胞 但未能形成髓鞘轴突，因为它们错误地将P0定位于非髓鞘表面 膜。具体目标1的研究将调查负责的机制 用于P0和MAG体外靶向MDCK细胞。特定目标2将 研究P0过度表达小鼠的髓鞘异常如何导致 PNS轴突中的离子通道分布和由以下组成的远端轴索病变 神经肌肉接头的轴突退出和随后的轴突 发芽和神经肌肉接头的再神经支配。我们还建立了 少突胶质细胞P0表达导致中枢神经系统髓鞘功能障碍和轴突 退化。《特殊目标3》将调查相关的分子机制 并确定表型是否被它们的 繁殖到PLP基因缺失的小鼠。总体而言，这些研究应该提供新的 髓鞘功能障碍的发病机制，分子机制 正常的髓鞘形成和髓鞘形成细胞的调节机制 轴突的发育和生存。

DESCRIPTION (provided by applicant): Myelin surrounds many of the axons in the central and peripheral nervous systems where it facilitates the rapid conduction of nerve impulses and provides an extrinsic trophic effect that promotes axonal maturation and survival. Dysmyelination and demyelination are major causes of neurological disability in humans and can be fatal. Historically, neurological deficits in these primary myelin diseases were thought to result from myelin pathology. However, recent studies have identified axonal degeneration in a number of primary myelin diseases. The most common causes of genetic myelin disease in humans are gene duplications that alter the dosage of myelin proteins. Much of what is known about the cellular and molecular aspects of normal myelination and the pathogenesis of inherited myelin diseases has been obtained from studies of rodents in which myelin protein genes are mutated, deleted or overexpressed. We have developed transgenic mouse models of PNS and CNS dysmyelination by overexpressing P0 protein, the major structural protein of PNS myelin in Schwann cells, and by expressing high levels of P0 protein in myelinating oligodendrocytes. The overall goal of this application is to understand how P0 overexpression causes myelin and axonal pathology. Schwann cells that overexpress P0 protein ensheath but fail to myelinate axons because they mistarget P0 to non-myelin surface membranes. Studies in Specific Aim 1 will investigate mechanisms responsible for P0 and MAG targeting in MDCK cells in vitro. Specific Aim 2 will investigate how dysmyelination in P0 overexpressing mice causes alteration in ion channel distribution in PNS axons and a distal axonopathy that consists of axonal withdrawal from the neuromuscular junction and subsequent axonal sprouting and neuromuscular junction reinnervation. We have also established that P0 expression by oligodendrocytes results in CNS dysmyelination and axonal degeneration. Specific Aim 3 will investigate molecular mechanisms responsible for these pathologies and determine if the phenotype is rescued by their breeding to PLP null mice. Collectively, these studies should provide novel information about the pathogenesis of dysmyelination, molecular mechanisms of normal myelination, and the mechanisms by which myelin-forming cells modulate the development and survival of axons.