与ALS相关的TDP-43M337V突变以性别特异性的方式使小胶质细胞衍生的细胞外microRNA失调。

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI:10.1242/dmm.050638
Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast
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引用次数: 0

摘要

有证据表明,在肌萎缩性脊髓侧索硬化症(ALS)这种最常见的成人运动神经元疾病中存在小胶质细胞活化和 microRNA(miRNA)失调。然而,很少有研究调查 miRNA 失调是否可能源于小胶质细胞。此外,参与 miRNA 生物发生的 TDP-43 在 98% 的 ALS 病例的组织中聚集。因此,本研究旨在确定与 ALS 相关的 TDP-43M337V 突变在转基因小鼠模型中的表达是否会导致小胶质细胞来源的 miRNA 失调。RNA 测序确定了转基因小胶质细胞释放的几种失调 miRNA,以及脂多糖刺激的小胶质细胞释放的不同 miRNA,其中雌性小鼠的细胞释放的 miRNA 更明显。我们通过反转录酶定量聚合酶链反应(RT-qPCR)验证了三个候选 miRNA(miR-16-5p、miR-99a-5p 和 miR-191-5p)的下调,并确定了它们的预测靶标,其中主要包括参与神经元发育和功能的基因。这些结果表明,TDP-43 功能的改变会导致小胶质细胞释放的 miRNA 群体发生变化,而这又可能是该疾病中观察到的 miRNA 失调的来源。这对神经炎症在渐冻症病理学中的作用具有重要意义,并可能提供潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.

Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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