Du Muzi, Akerman Suleyman C, Fare Charlotte M, Ruan Linhao, Vidensky Svetlana, Mamedova Lyudmila, Lee Joshua, Rothstein Jeffrey D
Johns Hopkins University School of Medicine.
Res Sq. 2024 Nov 19:rs.3.rs-5306005. doi: 10.21203/rs.3.rs-5306005/v1.
TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.
跨膜蛋白106B（TMEM106B）是一种溶酶体/晚期内体蛋白，是多种神经退行性疾病以及一般衰老过程中的强效基因修饰因子。最近，TMEM106B在死后人类脑组织中形成不溶性聚集体，这引起了人们对TMEM106B病理学以及TMEM106B聚集在疾病中的潜在作用的关注。在神经退行性疾病的背景下，已使用神经退行性疾病动物模型对TMEM106B进行了研究，但这些研究依赖于过表达或敲低方法。迄今为止，尚未报道动物模型中内源性TMEM106B病理学及其与已知经典病理学的关系。在这里，我们分析了与C9型肌萎缩侧索硬化症和额颞叶痴呆（C9-ALS/FTD）、与超氧化物歧化酶1（SOD1）相关的肌萎缩侧索硬化症以及tau蛋白病相关的小鼠模型中TMEM106B的组织学模式，并将其与C9-ALS/FTD、阿尔茨海默病（AD）以及伴有边缘叶为主的年龄相关性TDP-43脑病的AD（AD/LATE）患者的死后人体组织进行比较。我们表明，小鼠模型中的TMEM106B病理学与人类患者组织之间存在显著差异。重要的是，我们还从鼠模型和人类患者中都发现了趋同证据，将TMEM106B病理学与特别是在C9-ALS中的TDP-43核清除联系起来。同样，我们在阿尔茨海默病中发现了TMEM106B病理学与磷酸化Tau负担之间在细胞水平上的关系。通过表征小鼠和人类死后组织中的内源性TMEM106B病理学，我们的工作揭示了在分析小鼠研究数据时必须考虑的因素，并阐明了支持TMEM106B参与多种神经退行性疾病发病机制和进展的新见解。
