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，其特征是 运动神经元的进行性变性和上下运动的最终衰竭 系统。许多基因突变与肌萎缩侧索硬化症有关，但疾病机制 仍然难以捉摸。过去研究的大量证据表明，与肌萎缩侧索硬化症相关的突变 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。鉴于星形胶质细胞和小胶质细胞 作为神经毒性的潜在来源的广泛调查的焦点，其他神经胶质细胞 直到最近才得到充分的考虑。少突胶质细胞，髓鞘形成 中枢神经胶质细胞，为神经元提供代谢和营养支持，它们经历了大量的 在这种疾病的过程中，运动神经元胞体附近的变性。这 少突胶质细胞的病理一定很重要，因为突变体的选择性失活 少突胶质细胞的表达明显减轻了疾病的症状和进展 当同样的操作被应用于其他神经细胞群体时。这项提案将把重点放在 体内少突胶质细胞功能障碍的细胞机制及其不良影响 对肌萎缩侧索硬化症小鼠运动神经元存活的影响。首先，我们将确定相对时间和 少突胶质细胞变性与运动神经元死亡的因果关系 控制自然的少突胶质细胞再生。第二，使用新开发的细胞 表达SOD1(G93A)的小鼠，我们将定义细胞固有的，分子异常的 少突胶质细胞与少突胶质细胞特异性SOD1后的病程 (G93A)表达。第三，我们将确定是否促进少突胶质细胞再生 髓鞘再生可作为ALS的一种新的治疗策略。通过这些 实验中，我们将研究以前ALS的一个重要的支持神经胶质细胞群体 长期以来，研究一直忽视这一点。结果将决定中枢神经系统髓鞘胶质细胞是否是 ALS中的关键角色或修饰者，说明少突胶质细胞特有的分子通路 促进肌萎缩侧索硬化症的病理生理学，并评估少突胶质细胞引导的再生 尽可能采用ALS治疗方法。通过这个项目，我们还将添加一个新的鼠标 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.