Pathological myelin outfoldings: cellular cause and behavioral consequences

病理性髓鞘外折叠：细胞原因和行为后果

• 批准号: 235212738
• 负责人: Privatdozent Dr. Hauke Werner
• 金额: --
• 依托单位: Abteilung Neurogenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/235212738?language=en
• 关键词: Pathological; myelin; outfoldings; cellular; cause

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.

轴突的髓鞘化促进神经系统中快速和精确的脉冲传播，这是正常运动、感觉和认知能力的先决条件。轴突/髓鞘单位在髓鞘相关病症中和在正常老化时受损。然而，许多病理特征的分子原因和功能后果仍然未知，包括经常观察到的髓鞘外折叠。我们已经确定了一个以前未被认识的结构，在中枢神经系统，髓鞘隔丝，纵向延伸沿着有髓轴突。在Sept 8突变小鼠中这些纤维的遗传破坏导致髓鞘外折叠作为一种非常特异的神经病理学。因此，需要在髓鞘成熟期间组装隔蛋白丝以支撑轴突/髓鞘单元。基于我们以前的观察，我们建议调查介导组装的髓鞘septins的分子因素，驱动髓鞘外折叠的形成的细胞力量及其在行为水平上的后果。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。Sept 8突变小鼠提供了一个独特的模型来测试这一假设，即由于髓鞘外折叠导致的神经传导速度降低足以导致行为障碍，包括在精神疾病中观察到的异常;这一新的概念将在体内进行测试。