Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type 
II transmembrane protein 106B increase the risk for frontotemporal lobar 
degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it 
is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if 
a gain or a loss of function of TMEM106B is responsible for the increased 
disease risk of patients with GRN haploinsufficiency. We therefore compare 
behavioral abnormalities, gene expression patterns, lysosomal activity, and 
TDP-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 
single Grn-/- knockouts only occasionally show TDP-43 pathology, the double 
knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of 
function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced 
protein turnover in the lysosomal/autophagic system.