Role of Oligodendroglia in the Pathogenesis of ALS

少突胶质细胞在 ALS 发病机制中的作用

• 批准号: 10011867
• 负责人: Shin H Kang
• 金额: $ 34.01万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011867
• 关键词: Address; Adult; Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Autopsy; Benztropine; Cell Communication; Cells; Central Nervous System Diseases; DNA Sequence Alteration; Diagnosis; Disease; Disease Outcome; Disease Progression; Environment; Event; Failure; Functional disorder; Genes; Human; Impairment; Investigation; Knowledge; Life; Link; Metabolic; Microglia; Molecular; Molecular Abnormality; Motor; Motor Neurons; Mus; Mutant Strains Mice; Natural regeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Nutritional Support; Oligodendroglia; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pharmacology; Play; Population; Resources; Role; Secondary to; Severity of illness; Signal Pathway; Source; Symptoms; System; Testing; Toxic effect; Transgenic Mice; cell type; disease mechanisms study; disease phenotype; effective therapy; experimental study; genetic manipulation; in vivo; insight; motor neuron degeneration; mouse genetics; mouse model; mutant; myelination; neglect; neuron loss; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; oligodendrocyte progenitor; regenerative; remyelination; superoxide dismutase 1; targeted treatment; therapeutic target; tool

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.

项目摘要 肌萎缩性外侧硬化症（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部和下运动的最终失败 系统。许多遗传突变已与ALS有关，但是疾病机制 仍然难以捉摸。过去研究的大量证据表明，ALS连接的突变体 - 表达神经胶质细胞形成神经毒性环境，从而在运动中起关键作用 神经元变性和疾病进展。而星形胶质细胞和小胶质细胞已经 广泛研究作为神经毒性的潜在来源的重点，其他神经胶质细胞 直到最近才得到足够的考虑。少突胶质细胞，骨髓 中枢神经系统神经胶质，为神经元提供代谢和营养支持，并且会大规模接受 在这种疾病过程中，运动神经元细胞体附近的变性。这 少突齿病理必须很重要，因为突变体的选择性失活 少突胶质细胞的表达减少了疾病症状，进展明显远远超过 当将相同的操作应用于其他神经细胞群体时。该建议将集中 关于体内寡头功能障碍的细胞机制及其有害影响 在ALS小鼠模型中的运动神经元存活上。首先，我们将确定相对时机和 通过少突胶质细胞变性与运动神经元死亡之间的因果关系 控制天然的寡胶质细胞再生。其次，使用新开发的细胞 表达小鼠的特定SOD1（G93A），我们将定义细胞内部，分子异常 少突胶质细胞和少突胶质特异性SOD1之后的疾病进展。 （G93a）表达。第三，我们将确定是否促进了少突胶质细胞再生 透明度可以作为ALS的新型治疗策略。通过这些 实验，我们将研究一个重要的支持神经胶质种群 研究长期以来一直被忽略。结果将确定CNS髓质神经胶质是否为 关键播放器或ALS中的修饰符说明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指导的再生 尽可能地接近ALS治疗。通过这个项目，我们还将添加一个新颖的鼠标 细胞类型特异性的遗传工具，体内研究ALS的疾病机制。

项目成果

Age and Alzheimer's Disease-Related Oligodendrocyte Changes in Hippocampal Subregions.

• DOI: 10.3389/fncel.2022.847097
• 发表时间: 2022
• 期刊: FRONTIERS IN CELLULAR NEUROSCIENCE
• 影响因子: 5.3
• 作者: DeFlitch, Leah;Gonzalez-Fernandez, Estibaliz;Crawley, Ilan;Kang, Shin H.
• 通讯作者: Kang, Shin H.

GluA2 overexpression in oligodendrocyte progenitors promotes postinjury oligodendrocyte regeneration.

• DOI: 10.1016/j.celrep.2021.109147
• 发表时间: 2021-05-18
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Khawaja RR;Agarwal A;Fukaya M;Jeong HK;Gross S;Gonzalez-Fernandez E;Soboloff J;Bergles DE;Kang SH
• 通讯作者: Kang SH