MOLECULAR MECHANISMS OF SCHWANN CELL MYELINATION

髓磷脂围绕中枢和外周神经元系统中的许多轴突，在那里它促进神经冲动的快速传导，并提供促进轴突成熟和存活的外源性营养作用。 髓鞘形成失败和成熟髓鞘的破坏是人类神经功能障碍的主要原因，并且可能是致命的。从历史上看，这些原发性髓鞘疾病的神经功能缺损被认为是髓鞘病理学的结果。 然而，最近的研究已经确定了大量的原发性髓鞘疾病的轴突变性。 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、重复和缺失。 人类遗传性髓鞘疾病最常见的原因是基因复制改变髓鞘蛋白的剂量。 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已经从啮齿动物的研究中获得，其中髓鞘蛋白基因突变、缺失或过表达。我们通过1）在施万细胞中过表达P0蛋白（PNS髓鞘的主要结构蛋白）和2）在髓鞘形成的少突胶质细胞中表达高水平的P0蛋白，开发了PNS和中枢神经系统髓鞘发育障碍的转基因小鼠模型。 在P0过度表达的小鼠中，雪旺细胞不能形成髓鞘，因此，运动轴突退化。初步研究表明，髓鞘形成障碍的结果从错误的P0蛋白的非髓鞘表面膜。 《特定目标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形成障碍，包括多余的髓鞘膜和可能的轴突变性。 本提案的具体目标2中的研究将调查导致这种髓鞘形成障碍的分子机制，并比较和对比少突胶质细胞中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，这些研究应该提供新的信息，髓鞘形成障碍的发病机制，正常髓鞘形成的分子机制，以及髓鞘形成细胞调节轴突的发育和存活的机制。

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.