Pathogenesis of Neurological Disability in Primary Diseases of Myelin

摘要 获得性和遗传性髓鞘疾病是非创伤性神经系统疾病的主要原因。 美国年轻人的残疾。研究还描述了大脑中的髓鞘病理学 来自患有肌萎缩侧索硬化症（ALS）和阿尔茨海默病（AD）的个体，和 髓鞘蛋白基因等位基因是精神分裂症、抑郁症和自闭症的危险因素。在 因此，除了其绝缘特性之外，髓磷脂对神经元功能具有多种作用。它 现在公认轴突和神经元变性会导致永久性神经功能障碍 在患有原发性髓鞘疾病的个体中。我的实验室在鉴定 多发性硬化症（MS）患者脑中的轴突和神经元变性， 人类中枢神经系统（CNS）的炎性脱髓鞘疾病。我们利用 这些数据开发的动物模型，概括了髓鞘诱导的机制方面， 轴突和神经元变性。本建议的目的是巩固三个 NINDS R 01研究髓鞘诱导的神经变性机制。我们将 解决三个关键问题。1)髓磷脂如何为轴突提供营养支持？我们 提出ATP底物的转移是髓鞘提供 对轴突的营养支持遗传性髓鞘疾病中这种代谢偶联的破坏 诱导结旁轴浆中的线粒体病理/变性，这引起轴突 退化2)脱髓鞘如何影响神经元及其突触连接？我们 提出脱髓鞘改变神经元基因表达，调节树突结构， 降低神经元的活力;我们进一步提出髓鞘再生将逆转这些变化。第三章 软膜下皮质脱髓鞘是如何发生的？我们认为软膜下脱髓鞘发生在 通过不同于免疫介导的机制使白色物质脱髓鞘 并且需要新的疗法来预防软膜下脱髓鞘。最大的挑战 髓鞘研究界面临的是神经保护疗法的发展。R35 资金将巩固我们的努力，以确定新的治疗目标，造成轴突和 髓鞘疾病中的神经元变性。这对于发展 神经保护疗法，延迟并可能逆转永久性神经功能障碍， 患有髓鞘疾病的人。

ABSTRACT Acquired and inherited diseases of myelin are the major cause of non-traumatic neurological disability in young adults in the USA. Studies have also described myelin pathology in brains from individuals with amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and myelin protein gene alleles are risk factors for schizophrenia, depression, and autism. In addition to its insulating properties, therefore, myelin has multiple effects on neuronal function. It is now accepted that axonal and neuronal degeneration cause permanent neurological disability in individuals with primary myelin disease. My laboratory played a significant role in identifying axonal and neuronal degeneration in brains from individuals with multiple sclerosis (MS), an inflammatory demyelinating disease of the human central nervous system (CNS). We leveraged these data to develop animal models that recapitulate mechanistic aspects of myelin-induced axonal and neuronal degeneration. The purpose of the present proposal is to consolidate three NINDS R01s that investigate mechanisms of myelin-induced neurodegeneration. We will address three key questions. 1) How does myelin provide trophic support to axons? We propose that transfer of ATP substrates is the major mechanism by which myelin provides trophic support to axons. Disruption of this metabolic coupling in inherited myelin diseases induces mitochondrial pathology/degeneration in paranodal axoplasm, which causes axonal degeneration. 2) How does demyelination affect neurons and their synaptic connections? We propose that demyelination alters neuronal gene expression, modulates dendritic structure, and reduces neuronal viability; we further propose that remyelination will reverse these changes. 3) How does subpial cortical demyelination occur? We propose that subpial demyelination occurs by mechanisms that differ from immune-mediated mechanisms that demyelinate white matter and that novel therapies are needed to prevent subpial demyelination. The biggest challenge facing the myelin research community is the development of neuroprotective therapies. R35 funding will consolidate our efforts to identify new therapeutic targets that cause axonal and neuronal degeneration in myelin diseases. This is essential for the development of neuroprotective therapies that delay and possibly reverse permanent neurological disability in individuals with myelin disease.