Group of Stem Cells and Modeling of Neurodegeneration, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 7, 1870C, Denmark.
Group of Stem Cells and Modeling of Neurodegeneration, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 7, 1870C, Denmark.
J Mol Biol. 2019 Apr 19;431(9):1818-1829. doi: 10.1016/j.jmb.2019.02.004. Epub 2019 Feb 11.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes that correlated with ALS and FTD are implicated in the same molecular pathways. Strikingly, many of these genes are not exclusively expressed in neurons, but also in glial cells, suggesting a multicellular pathogenesis. Moreover, chronic inflammation is a common feature observed in ALS and FTD, indicating an essential role of microglia, the resident immune cells of the central nervous system, in disease development and progression. In this review, we will provide a comprehensive overview of the implications of microglia in ALS and FTD. Specifically, we will focus on the role of impaired phagocytosis and increased inflammatory responses and their impact on microglial function. Several genes associated with the disorders can directly be linked to microglial activation, phagocytosis and neuroinflammation. Other genes associated with the disorders are implicated in biological pathways involved in protein degradation and autophagy. In general such mutations have been shown to cause abnormal protein accumulation and impaired autophagy. These impairments have previously been linked to affect the innate immune system in the central nervous system through inappropriate activation of microglia and neuroinflammation, highlighted in this review. Although it has been well established that microglia play essential roles in neurodegenerative disorders, the precise underlying mechanisms remain to be elucidated.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是具有明显相似临床、遗传和病理学特征的神经退行性疾病。这两种疾病都是进行性、致命性疾病，目前尚无有效的治疗方法。与 ALS 和 FTD 相关的几个基因与相同的分子途径有关。引人注目的是，这些基因中的许多不仅在神经元中表达，而且在神经胶质细胞中表达，提示存在多细胞发病机制。此外，慢性炎症是 ALS 和 FTD 中常见的特征，表明中枢神经系统的固有免疫细胞小胶质细胞在疾病发展和进展中起着重要作用。在这篇综述中，我们将全面概述小胶质细胞在 ALS 和 FTD 中的作用。具体而言，我们将重点关注吞噬作用受损和炎症反应增加及其对小胶质细胞功能的影响。与这些疾病相关的几个基因可以直接与小胶质细胞激活、吞噬作用和神经炎症相关联。与这些疾病相关的其他基因则涉及涉及蛋白质降解和自噬的生物学途径。一般来说，这些突变被认为会导致异常蛋白积累和自噬受损。在这篇综述中强调，这些缺陷以前曾通过小胶质细胞和神经炎症的不适当激活被认为会影响中枢神经系统的先天免疫系统。尽管已经清楚地表明小胶质细胞在神经退行性疾病中发挥着重要作用，但确切的潜在机制仍有待阐明。
