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. Overall design: 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.