Single nucleotide polymorphisms (SNPs) inTMEM106Bencoding the lysosomal typeIItransmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) ofGRN(progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) andTMEM106B are synergistically linked and if a gain or a loss of function ofTMEM106B is responsible for the increased disease risk of patients withGRNhaploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, andTDP-43 pathology in single and double knockout animals.Grn(-/-)/Tmem106b(-/-)mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while singleGrn(-/-)knockouts only occasionally showTDP-43 pathology, the double knockout mice exhibit deposition of phosphorylatedTDP-43. Thus, a loss of function ofTMEM106B may enhance the risk forGRN-associatedFTLDby reduced protein turnover in the lysosomal/autophagic system.