Molecular mechanisms of Schwann cell myelination

描述（由申请人提供）：髓鞘形成是正常轴突成熟所必需的，轴突的存活取决于髓鞘形成后少突胶质细胞和雪旺细胞的支持。在没有PLP的小鼠和PLP被P0蛋白取代的小鼠中出现晚发性轴突病和轴突变性。虽然轴突细胞骨架和轴突运输的改变先于这些小鼠的轴突变性，但髓鞘诱导的轴突病理的分子机制知之甚少。本提案的目的是确定髓磷脂如何调节轴突功能和存活。我们的研究基于这样的假设：髓磷脂调节轴突蛋白的翻译后修饰，维持微管稳定性和线粒体融合/裂变。特异性Aim 1主要关注最丰富的髓磷脂蛋白P0和PLP的作用，通过研究用PLP替代P0在髓鞘雪旺细胞中的作用。我们特别询问PLP是否可以取代P0作为致密PNS髓磷脂的结构蛋白，以及这是否对轴突的功能或存活有不利影响。特异性目的2通过研究P0-CNS小鼠轴突变性前的轴突细胞骨架变化，关注PLP在维持中枢神经系统轴突完整性中的作用。基于我们对微管长度、方向和稳定性改变的初步发现，这些研究旨在1)确定维持轴突细胞骨架的上游髓鞘-轴突信号事件，2)通过调节激酶和磷酸酶为轴突保护疗法的发展提供方向。具体目标3将研究髓磷脂如何调节轴突线粒体分布和运输。线粒体对正常的轴突功能至关重要，是跳跃传导和轴突运输所需ATP的主要来源。能量产生减少被认为是髓磷脂疾病中轴突变性的主要原因。轴突包含静止和运动的线粒体池。我们将研究野生型和P0-CNS小鼠髓鞘形成、脱髓鞘形成和髓鞘异常对线粒体运输、线粒体静止位点分布和线粒体融合/裂变的影响。初步数据支持这些研究的可行性，这应该提供髓磷脂对线粒体分布和运输的影响的第一个描述。这一知识对未来治疗髓磷脂疾病的轴突能量产生至关重要。

DESCRIPTION (provided by applicant): Myelination is required for normal axonal maturation, and axon survival depends upon oligodendrocyte and Schwann cell support after myelination. Late onset axonopathies and axonal degeneration develop in mice null for PLP and in mice where PLP was replaced by P0 protein. While alterations of axonal cytoskeleton and axonal transport precede axonal degeneration in these mice, little is known about the molecular mechanisms responsible for myelin-induced axonal pathology. The goal of this proposal is to determine how myelin modulates axonal function and survival. Our studies are based upon the hypothesis that myelin regulates post translational modifications of axonal proteins that maintain microtubule stability and mitochondrial fusion/fission. Specific Aim 1 is focused on the role of the most abundant myelin proteins, P0 and PLP, by investigating the effects of replacing P0 with PLP in myelinating Schwann cells. We specifically ask if PLP can replace P0 as the structural protein of compact PNS myelin, and if this has a detrimental effect on the function or survival of axons. Specific Aim 2 is focused on the role of PLP in maintaining CNS axonal integrity by investigating axonal cytoskeletal changes that precede axonal degeneration in P0-CNS mice. Based on our preliminary findings of altered microtubule length, orientation and stability, these studies are designed to 1) identify upstream myelin-axon signaling events that maintain the axonal cytoskeleton and 2) provide direction for the development of axon-protective therapies by modulation of kinases and phosphatases. Specific Aim 3 will investigate how myelin regulates axonal mitochondrial distribution and transport. Mitochondria are essential to normal axonal function and are the major source of the ATP needed for saltatory conduction and axonal transport. Reduced energy production is considered a major cause of axonal degeneration in diseases of myelin. Axons contain both stationary and motile mitochondrial pools. We will investigate the effects of myelination, demyelination and dysmyelination on mitochondrial transport, mitochondrial stationary site distribution and mitochondrial fusion/fission in wild type and P0-CNS mice. Preliminary data support the feasibility of these studies, which should provide the first description of the effects of myelin on mitochondrial distribution and transport. This knowledge is essential for future therapeutics that will target axonal energy production in diseases of myelin. PUBLIC HEALTH RELEVANCE: This project will continue to develop our knowledge of the role of myelin in neurological development and in neurodegenerative diseases. The results will contribute to understanding myelin disease pathology and provide clues for effective future therapeutic strategies for treating primary myelin diseases.