Pathological myelin outfoldings: cellular cause and behavioral consequences

轴突的髓鞘形成促进了神经系统中快速而准确的冲动传播，这是正常运动、感觉和认知能力的先决条件。在髓鞘相关疾病和正常衰老时，轴突/髓鞘单位会受损。然而，许多病理特征的分子原因和功能后果仍不清楚，包括经常观察到的髓鞘外折。我们在中枢神经系统中发现了一种以前未被发现的结构，髓鞘隔蛋白细丝，它沿着有髓轴突纵向延伸。在9月8日突变的小鼠中，这些细丝的遗传破坏导致了髓鞘外折叠，这是一种非常特殊的神经病理。因此，在髓鞘成熟过程中，隔膜细丝的组装是构建轴突/髓鞘单位所必需的。基于我们以前的观察，我们建议在行为水平上研究介导髓鞘间隔蛋白组装的分子因素，驱动髓鞘外折叠形成的细胞力及其后果。该项目将涉及小鼠遗传学、生物化学、定量蛋白质组学、电子显微镜和小鼠行为评估。9月8日-突变小鼠提供了一个独特的模型来测试这一假设，即髓鞘外折导致的神经传导速度降低足以导致行为障碍，包括精神疾病中的异常；这一新概念将在体内进行测试。

Myelination of axons facilitates rapid and precise impulse propagation in the nervous system, a prerequisite for normal motor, sensory and cognitive capabilities. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular causes and functional consequences of many pathological features have remained unknown, including the frequently observed myelin outfoldings. We have identified a previously unrecognized structure in the central nervous system, myelin septin filaments, which extend longitudinally along myelinated axons. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. The assembly of septin filaments during the maturation of myelin is thus required to scaffold the axon/myelin-unit. Based on our previous observations we propose to investigate the molecular factors mediating the assembly of myelin septins, the cellular forces driving the formation of myelin outfoldings and their consequences at the behavioral level. This project will involve mouse genetics, biochemistry, quantitative proteomics, electron microscopy and assessment of mouse behavior. Sept8-mutant mice provide a unique model to test the hypothesis that the reduced nerve conduction velocity due to myelin outfoldings is sufficient to cause behavioral impairment including abnormalities seen in psychiatric conditions; this novel concept will be tested in vivo.