神经退行性变
疾病
人类疾病
人体病理学
病理
神经科学
医学
生物
作者
Muzi Du,Sigvard Åkerman,Charlotte M. Fare,Linhao Ruan,Svetlana Vidensky,Л. Н. Мамедова,Joshua D. Lee,Jeffrey D. Rothstein
标识
DOI:10.1101/2024.10.16.618765
摘要
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 in vivo 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 C9ORF72-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, Alzheimers 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, however, 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 profound relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimers disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals essential considerations that must be taken when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.
科研通智能强力驱动
Strongly Powered by AbleSci AI