Progranulin (GRN) and TMEM106B are associated with several common
neurodegenerative disorders including
frontotemporal lobar degeneration (
FTLD). A TMEM106B variant modifies GRN-associated
FTLD risk. However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn-/- and Tmem106b-/- mice, we show that, while multiple lysosomal
enzymes are increased in Grn-/- brain at both transcriptional and
protein levels, TMEM106B deficiency causes reduction in several lysosomal
enzymes. Remarkably, Tmem106b deletion from Grn-/- mice normalizes lysosomal
protein levels and rescues
FTLD-related behavioral abnormalities and
retinal degeneration without improving
lipofuscin, C1q, and microglial accumulation. Mechanistically, TMEM106B binds
vacuolar-ATPase accessory
protein 1 (AP1). TMEM106B deficiency reduces
vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal
protein levels in Grn-/- neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal
enzyme levels, and their interaction determines the extent of neurodegeneration.