Role of Oligodendroglia in the Pathogenesis of ALS

项目摘要 肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征在于： 运动神经元的进行性退化和上下运动神经元的最终衰竭 系统.许多基因突变与ALS有关，但疾病机制 仍然难以捉摸过去研究的大量证据表明，ALS相关的突变体- 表达神经胶质细胞形成神经毒性环境，从而在运动中发挥关键作用。 神经元变性和疾病进展。而星形胶质细胞和小胶质细胞 作为神经毒性的潜在来源，其他神经胶质细胞 直到最近才得到充分考虑。少突胶质细胞， 中枢神经系统胶质细胞为神经元提供代谢和营养支持， 在这种疾病的过程中，运动神经元细胞体附近发生变性。这 少突胶质细胞病理学必须是显著的，因为突变体的选择性失活 少突胶质细胞的表达显著减少疾病症状和进展， 当同样的操作应用于其他神经细胞群体时。该提案将重点 体内少突胶质细胞功能障碍的细胞机制及其有害影响 运动神经元存活的影响。首先，我们将确定相对时间， 少突胶质细胞变性和运动神经元死亡之间的因果关系 控制少突胶质细胞的自然再生第二，使用新开发的细胞， 特异性Sod 1（G93 A）表达小鼠，我们将定义细胞内在的，分子异常， 少突胶质细胞特异性Sod 1后的疾病进展过程 （G93 A）表达。第三，我们将确定是否促进少突胶质细胞再生， 和髓鞘再生可以作为ALS的一种新的治疗策略。通过这些 实验中，我们将研究一个重要的支持神经胶质细胞的人口，以前的ALS 研究长期以来一直被忽视。结果将决定中枢神经系统髓鞘神经胶质细胞是否是一个 ALS中关键参与者或修饰者，阐明了少突胶质细胞特异性分子途径 有助于ALS病理生理学，并评估少突胶质细胞定向再生 尽可能的治疗ALS。通过这个项目，我们还将增加一个新颖的鼠标 用于ALS疾病机制的细胞类型特异性体内研究的遗传工具。

Project Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons and the eventual failure of upper and lower motor systems. Numerous genetic mutations have been linked to ALS, but the disease mechanism remains elusive. A large body of evidence from past studies suggests that ALS-linked, mutant- expressing glial cells form a neurotoxic environment, and thereby play a critical role in motor neuron degeneration and disease progression. Whereas astrocytes and microglia have been the focus of extensive investigation as potential sources of the neurotoxicity, other glial cells have not been given adequate consideration until recently. Oligodendrocytes, the myelinating CNS glia, provide metabolic and nutritional support to neurons, and they undergo massive degeneration near motor neuron cell bodies during the course of this disease. This oligodendroglial pathology must be significant, because selective inactivation of the mutant expression of oligodendroglia reduces disease symptoms and progression markedly more than when the same manipulation is applied to other neural cell populations. This proposal will focus on the cellular mechanisms of oligodendroglial dysfunction in vivo, and their detrimental impact on motor neuron survival in mouse models of ALS. First, we will identify the relative timing and causal relationship between oligodendrocyte degeneration and motor neuron death by controlling the natural oligodendrocyte regeneration. Second, using newly developed, cell specific Sod1 (G93A) expressing mice, we will define cell-intrinsic, molecular abnormalities of oligodendrocytes and the course of disease progression after oligodendroglia-specific Sod1 (G93A) expression. Third, we will determine whether promoted oligodendrocyte regeneration and remyelination can serve as a novel therapeutic strategy for ALS. Through these experiments, we will investigate an important supporting glial population that previous ALS studies have long ignored. The outcomes will determine whether the CNS myelinating glia are a key player or a modifier in ALS, illustrate oligodendrocyte-specific molecular pathways contributing to ALS pathophysiology, and evaluate oligodendrocyte-directed regenerative approaches as possible ALS treatments. Through this project we will also add a novel mouse genetic tool for cell-type specific, in vivo studies of the disease mechanisms of ALS.