TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy

TMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimer's and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding variant found in the minor haplotype contributes to protection, and whether the presence of TMEM106B is helpful or harmful in the context of disease. Here we address both issues while extending the testbed for study of TMEM106B from models of TDP to tauopathy. We show that TMEM106B deletion accelerates cognitive decline, hindlimb paralysis, neuropathology, and neurodegeneration. TMEM106B deletion also increases transcriptional overlap with human AD, making it a better model of disease than tau alone. In contrast, the coding variant protects against tau-associated cognitive decline, neurodegeneration, and paralysis without affecting tau pathology. Our findings show that the coding variant contributes to neuroprotection and suggest that TMEM106B is a critical safeguard against tau aggregation. Two cohorts were studied, each containing 4 genotypes of mice.The first cohort was generated by intercrossing TMEM106B tm2d deletion mice with MAPT-P301S transgenic mice (line PS19).The second cohort was generated by intercrossing TMEM106B T186S knockin mice with MAPT-P301S transgenic mice (line PS19).Two variables are tested in each cohort.Variable number 1 is the TMEM106B genotype:WT, KO, or KI.KO and KI mice are homozygous for the respective allele.Variable number 2 is the presence or absence of transgenic MAPT (tau). Tau mice are heterozygous for the MAPT transgene."_O" or "_I" designation is used when a shared genotype (WT or tau alone) arose from the KO or KI colony, respectively.Both cohorts were bred on a hybrid C3B6 strain background.TMEM106B是一类不断增多的年龄相关性痴呆（包括阿尔茨海默病（Alzheimer's）与额颞叶痴呆（frontotemporal dementia））的风险修饰因子，但其具体生物学功能仍未明确。既往相关研究引出两个核心科学问题：次要单倍型中检出的保守型T185S编码变体是否参与疾病保护，以及TMEM106B的存在对疾病进程究竟发挥有益还是有害的作用。本研究同时解答了这两个问题，并将TMEM106B的研究模型体系从TDP相关模型拓展至tau蛋白病（tauopathy）模型。本研究证实，TMEM106B敲除会显著加速认知衰退、后肢麻痹、神经病理损伤与神经退行性变进程；此外，TMEM106B敲除还会提升小鼠模型与人类阿尔茨海默病的转录组重叠度，使其成为优于单纯tau过表达模型的疾病研究载体。与之形成鲜明对比的是，该T185S编码变体可有效抵御tau介导的认知衰退、神经退行性变与麻痹，且不会对tau病理进程产生影响。本研究结果表明，该编码变体具有明确的神经保护作用，同时提示TMEM106B是抵御tau蛋白聚集的关键保护性因子。 本研究共纳入两个独立队列，每个队列均包含4种小鼠基因型组合。第一队列通过将TMEM106B tm2d敲除小鼠与MAPT-P301S转基因小鼠（PS19品系）杂交繁育获得；第二队列则通过将TMEM106B T186S敲入小鼠与MAPT-P301S转基因小鼠（PS19品系）杂交繁育获得。每个队列均设置两个实验变量：变量1为TMEM106B基因型，分为野生型（WT）、敲除型（KO）与敲入型（KI），其中KO与KI小鼠均为对应等位基因的纯合个体；变量2为是否携带转基因MAPT（即tau蛋白），携带tau的小鼠为MAPT转基因杂合子。当共享基因型（仅野生型或仅tau单基因型）分别源自KO或KI繁育群时，分别采用“_O”或“_I”进行标注区分。两个队列的繁育均采用C3B6杂交品系作为遗传背景。