Molecular Mechanisms of Schwann Cell Myelination

描述（由申请人提供）：髓磷脂围绕着神经元中的许多轴突。 中枢和周围神经系统，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作用， 促进轴突成熟和存活。髓鞘异常和脱髓鞘是 是人类神经系统残疾的主要原因，可能是致命的。 从历史上看，这些原发性髓鞘疾病的神经功能缺损是 被认为是髓鞘病变的结果。但最近的研究 在许多原发性髓鞘疾病中发现了轴突变性。最 人类遗传性髓鞘疾病的常见原因是基因复制， 改变髓鞘蛋白的剂量。关于细胞的大部分知识 正常髓鞘形成的分子方面和遗传性 髓磷脂疾病已经从啮齿动物的研究中获得， 蛋白质基因突变、缺失或过表达。我们已经开发 通过过表达P0的PNS和CNS髓鞘形成障碍的转基因小鼠模型 蛋白，PNS髓鞘在雪旺细胞中的主要结构蛋白， 在有髓鞘的少突胶质细胞中表达高水平的P0蛋白。的 本申请的总体目标是了解P0过表达如何导致 髓鞘和轴突病理学。过表达P0蛋白包被的雪旺细胞 但由于它们将P0错误地指向非髓鞘表面， 膜。具体目标1中的研究将调查 用于体外MDCK细胞中的P0和MAG靶向。具体目标2将 研究P0过度表达小鼠的髓鞘形成障碍如何导致 PNS轴突中的离子通道分布和远端轴突病，包括 轴突从神经肌肉接头退出， 发芽和神经肌肉接头再神经支配。我们还建立 少突胶质细胞表达P0导致CNS髓鞘形成障碍和轴突再生障碍， 退化具体目标3将研究分子机制负责 并确定表型是否被其 繁殖至PLP缺失小鼠。总的来说，这些研究应该提供新的 关于髓鞘形成障碍的发病机制， 正常的髓鞘形成，以及髓鞘形成细胞调节 轴突的发育和存活。

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.