MOLECULAR MECHANISM OF SCHWANN CELL MYELINATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在脊椎动物神经系统中，髓鞘是包裹在轴突周围的多层绝缘膜，促进神经的快速交流。我们正在研究在中枢神经胶质细胞中表达P0而不是PLP的基因工程小鼠。令人惊讶的是，在缺乏PLP的情况下，P0为小鼠中枢神经系统髓磷脂提供了良好的有序结构，但有序结构与哺乳动物外周神经系统（PNS）髓磷脂相似，其中P0是主要结构蛋白。因此，PLP和P0的存在与否似乎决定了髓磷脂的有序结构。然而，这些小鼠的寿命减少了50%，可能是因为轴突变性。CNS髓磷脂中含有等量P0和PLP的小鼠寿命正常，无轴突变性。提出的调查的目的是阐明在轴突变性之前有髓鞘轴突的变化。初步研究表明，在Ranvier淋巴结或附近的轴突运输发生了变化。我们怀疑轴突细胞骨架的三维组织在节区发生了改变。这个假设可以用高压显微镜和NCMIR常规使用的厚切片来检验。第二个项目涉及观察多发性硬化症（MS）患者的脊髓，慢性脱髓鞘轴突的退化是MS患者不可逆转的神经功能残疾的主要原因。神经保护疗法的发展将需要阐明神经元和轴突退化的分子机制。珀金斯博士将帮助我们描述线粒体的结构异常存在于MS脊髓使用电子断层扫描。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. IIn the vertebrate nervous system, myelin is a multilayer membrane insulation that surrounds axons and promotes rapid nerve communication. We are investigating genetically engineered mice that express P0 instead of PLP in CNS glia. Surprisingly, in the absence of PLP, P0 provided a well ordered structure to mouse CNS myelin, but the ordered structure resembled that found in mammalian peripheral nervous system (PNS) myelin where P0 is the major structural protein. Thus, the presence or absence of PLP and P0 appears to define the ordered structure of myelin. However, the lifespan of these mice was reduced by 50%, presumably because of the axonal degeneration. Mice with equal amounts of P0 and PLP in CNS myelin had normal lifespans and no axonal degeneration. The purpose of the proposed investigation is to elucidate changes in the myelinated axon that precede axonal degeneration. Preliminary studies indicate alterations in the axonal transport at or near nodes of Ranvier. We suspect that the 3-dimentional organization of axonal cytoskeleton is altered in nodal regions. This hypothesis can be tested with the high voltage microscope and thick sections routinely used at the NCMIR. A second project involves looking at the spinal cord from multiple sclerosis (MS) patients Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in MS patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate. Dr. Perkins will help us to characterize the structural abnormalities of mitochondria present in MS spinal cord using electron tomography.