Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD–GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. iMGs from FTD–GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD–GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.

中文翻译：

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颗粒体蛋白前体单倍体不足介导人小胶质细胞中胞质 TDP-43 聚集和溶酶体异常

由于颗粒体蛋白前体基因 (GRN) 变异导致的颗粒体蛋白前体 (PGRN) 单倍体不足可导致额颞叶痴呆 (FTD)，并伴有异常的 TAR DNA 结合蛋白 43 (TDP-43) 积累。尽管小胶质细胞负担与TDP-43相关的病理生理学有关，但直接的小胶质细胞TDP-43病理学尚未阐明，仅在神经元病理学中强调。因此，本研究的目的是调查 PGRN 单倍体不足患者小胶质细胞中的 TDP-43 病理学。为了设计具有 PGRN 单倍体不足的人类小胶质细胞模型，从携带致病或可能致病变异（p.M1？和 p.W147*）的 FTD-GRN 患者和三名健康对照中产生单核细胞衍生的小胶质细胞（iMG）。 PGRN 缺乏的 FTD-GRN 患者的 iMG 表现出严重的神经炎症表型，无法维持其稳态分子特征，同时吞噬作用受损。在 FTD-GRN 患者来源的 iMG 中，观察到显着的细胞质 TDP-43 聚集和脂滴积累，并伴有严重的溶酶体异常。这些病理机制是由补体 C1q 激活和促炎细胞因子上调介导的。我们的研究提供了大量的细胞和分子证据，表明人类小胶质细胞中GRN的功能丧失变异可导致小胶质细胞功能障碍，炎症环境以及受损的溶酶体诱导TDP-43异常聚集。阐明小胶质细胞 TDP-43 病理学在因 PGRN 缺乏而加剧 FTD 个体神经炎症中的作用，并检查对小胶质细胞功能障碍的相应影响，可能会对 FTD 和神经退行性疾病的潜在机制产生新的见解。