Axonal Pathology in Multiple Sclerosis

轴索变性是导致不可逆神经功能障碍患者多发的主要原因 患有硬化症(MS)。先前对多发性硬化症患者的大脑和脊髓进行的尸检已经确定了三种情况，即轴突和神经元变性。1)炎性脱髓鞘过程中轴突被切断。2)大脑皮层脱髓鞘横断轴突和树突，导致神经元凋亡。3)慢性脱髓鞘轴突变性。这个项目的总体目标是通过深入了解慢性脱髓鞘轴突退化的分子机制来扩展我们之前的研究。这些知识对于神经保护疗法的发展至关重要，这种疗法将阻止或延缓多发性硬化症患者神经功能障碍的持续发展。我们的研究基于这样一种假设，即轴膜分子组成的改变和线粒体功能的降低引发了轴突变化的恶性循环，而这种变化不是神经元或慢性脱髓鞘轴突所能控制的。能量减少会抑制轴突运输和线粒体更新，从而进一步减少能量的产生。通过脱髓鞘轴突进行神经传导的能量需求无法满足，导致一系列离子失衡，从而增加轴突钙离子，破坏轴突。我们的研究分为两个具体目标。第一个将继续检查死后的MS大脑和脊髓，通过表征化学脱髓鞘轴突中蛋白质的组成和分布，确定轴突线粒体的分布和功能状态，以及 通过表征反映或有助于改变轴突运输和轴突退化的轴突细胞器。第二个目的是在慢性轴索变性的动物模型中直接测试我们假设的各个方面。总的来说，这些研究应该确定可以阻止或延缓MS患者神经退行性变的治疗靶点。

Axonal degeneration is the major cause irreversible neurological disability patients multiple of in with sclerosis (MS). Previous examination of postmortem MS brains and spinal cords has identified three settings of axonal and neuronal degeneration. 1) Axons are transected during inflammatory demyelination. 2) Demyelination of the cerebral cortex transects axons and dendrites and causes neuronal apoptosis. 3) Chronically demyelinated axons degenerate. The overall goal of this project is to extend our previous studies by gaining insight, into the molecular mechanisms responsible for degeneration of chronically demyelinated axons. Such knowledge is essential for the development of neuroprotective therapeutics that will stop or delay the relentless progression of neurological disability in MS patients. Our studies are based upon the hypothesis that alterations in the molecular composition of the axolemma and reduced mitochrondrial function initiate a vicious cycle of axonal changes that cannot be controlled by the neuron or chronically demyelinated axon. Reduced energy inhibits axonal transport and mitochrondrial renewal which further decreases energy production. The increased energy demands of nerve conduction through demyelinated axons cannot be met resulting in a series of ionic imbalances that increases axonal calcium and destroys the axon. Our studies are divided into two Specific Aims. The first will continue to examine postmortem MS brains and spinal cords by characterizing the composition and distribution of proteins in the chemically demyelinated axon, determining the distribution and functional status of axonal mitochrondria and by characterizing axonal organelles that reflect or contribute to altered axon transport and to axonal degeneration. The second aim is designed to directly test various aspects of our hypothesis in an animal model of chronic axonal degeneration. Collectively, these studies should identify therapeutic targets that could stop or delay neurodegeneration in MS patients.