MOLECULAR MECHANISMS OF SCHWANN CELL MYELINATION

髓磷脂包围着中枢和外周神经元系统的许多轴突，在那里它促进神经冲动的快速传导，并提供一种促进轴突成熟和存活的外在营养效应。髓磷脂形成失败和成熟髓磷脂的破坏是人类神经功能障碍的主要原因，可能是致命的。历史上，这些原发性髓鞘疾病的神经功能缺损被认为是髓鞘病理所致。然而，最近的研究已经在大量的原发性髓鞘疾病中发现了轴突变性。髓磷脂蛋白基因的突变是许多髓磷脂疾病的原因。这些包括点突变、终止密码子、复制和缺失。人类遗传性髓磷脂疾病最常见的原因是基因复制改变了髓磷脂蛋白的剂量。关于正常髓鞘形成的细胞和分子方面以及遗传性髓鞘疾病的发病机制的许多已知信息都是从对髓鞘蛋白基因突变、缺失或过度表达的啮齿动物的研究中获得的。我们通过在雪旺细胞中过表达PNS髓磷脂的主要结构蛋白P0蛋白，以及在髓鞘少突胶质细胞中高水平表达P0蛋白，建立了PNS和CNS髓鞘发育异常的转基因小鼠模型。过表达P0的小鼠的雪旺细胞不能形成髓鞘，因此运动轴突退化。初步研究表明，髓鞘发育异常是由于P0蛋白错靶到非髓鞘表面膜。具体目标1的研究将严格检验这一假设，并研究轴突退化的机制。P0在少突胶质细胞中的表达导致髓鞘发育异常，包括髓鞘膜冗余和可能的轴突变性。本课题Specific aim 2的研究将探讨这种髓鞘分化的分子机制，并比较少突胶质细胞中P0表达与少突胶质细胞中PLP过表达和雪旺细胞中P0过表达的影响。总的来说，这些研究应该为髓鞘发育异常的发病机制、正常髓鞘形成的分子机制以及髓鞘形成细胞调节轴突发育和存活的机制提供新的信息。

Myelin surrounds many of the axons in the central and peripheral neurons systems where it facilitates the rapid conduction of nerve impulses and provides an extrinsic trophic effect that promotes axonal maturation and survival. Failure to form myelin and destruction of mature myelin are major causes of neurological disability in humans and can be fatal. Historically, neurological deficits in these primary myelin disease were thought to result from myelin pathology. However, recent studies have identified axonal degeneration in large number of primary myelin diseases. Mutations in myelin protein genes are responsible for many myelin diseases. These include point mutations, stop codons, duplications and deletions. 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 over expressed. We have developed transgenic mouse models of PNS and CNS dysmyelination by 1) over expressing P0 protein, the major structural protein of PNS myelin in Schwann cells, and 2) expressing high levels of P0 protein in myelinating oligodendrocytes. Schwann cells in P0 over expressing mice fail to myelinate and, as a consequence, motor axons degenerate. Preliminary studies suggest that dysmyelination results from mistargeting of P0 protein to non-myelin surface membranes. Studies in Specific Aim 1 will rigorously test this hypothesis and investigate the mechanism by which axons degenerate. Expression of P0 in oligodendrocytes results in a dysmyelination that includes redundant myelin membranes and possible axonal degeneration. Studies in Specific aim 2 of this proposal will investigate the molecular mechanisms responsible for this dysmyelination and compare and contrast the effects of P0 expression in oligodendrocytes with PLP over expression in oligodendrocytes and P0 over expression in Schwann cells. Collectively, these studies should provide novel information about the pathogenesis of dysmyelination, molecular mechanism of normal myelination, and he mechanisms by which myelin-forming cells modulate the development and survival of axons.