TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Human iMG]. TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Human iMG]

Heterozygous mutations in the granulin (GRN) gene result in haploinsufficiency of the progranulin (PGRN) protein, a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in the TMEM106B gene have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants are associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. In vitro, TMEM106B deletion did not reverse transcriptomic and proteomic profiles in GRN-deficient microglia, with the exception of a small set of immune-related proteins in the NF-κB pathway. In vivo, neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated gene expression in sorted microglia, lipid abnormalities, or histopathology in Grn knock-out mice. Furthermore, Tmem106b reduction with antisense oligonucleotide (ASO) treatment was poorly tolerated in Grn knock-out mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTLD-GRN. Overall design: Comparative RNA-seq data for full deletion of TMEM106B in hiPSC-derived microglia with GRN deletion.

颗粒蛋白（granulin, GRN）基因的杂合突变会导致前颗粒蛋白（progranulin, PGRN）单倍体剂量不足，这是伴TDP-43聚集的额颞叶变性（frontotemporal lobar degeneration with TDP-43 aggregates, FTLD-TDP）的主要致病诱因。TMEM106B基因的多态性与GRN突变携带者的疾病风险显著相关；而具有保护作用的TMEM106B变异体与TMEM106B蛋白水平降低存在关联，这提示降低TMEM106B的表达水平或可成为FTLD的潜在治疗策略。本研究在GRN缺陷的小鼠模型及诱导多能干细胞（induced pluripotent stem cell, iPSC）来源的人类细胞模型中，探究了TMEM106B完全敲除与部分敲低的生物学效应。体外实验结果显示，TMEM106B敲除未能逆转GRN缺陷小胶质细胞的转录组与蛋白质组特征，仅核因子κB（nuclear factor κB, NF-κB）通路上的少量免疫相关蛋白出现表达改变。体内实验中，无论是纯合还是杂合Tmem106b敲除，均未能使GRN基因敲除小鼠体内分选得到的小胶质细胞的疾病相关基因表达、脂质代谢异常及组织病理学特征恢复至正常水平。此外，通过反义寡核苷酸（antisense oligonucleotide, ASO）介导的Tmem106b敲低在GRN基因敲除小鼠中耐受性较差。本研究结果为小胶质细胞中TMEM106B与GRN的功能调控机制提供了新的认知，但并不支持将降低TMEM106B水平作为治疗FTLD-GRN的可行治疗策略。实验整体设计：针对携带GRN基因敲除的人类诱导多能干细胞（human induced pluripotent stem cell, hiPSC）来源的小胶质细胞，获取其TMEM106B完全敲除后的对比转录组测序（RNA-seq）数据。