Progranulin haploinsufficiency disrupts cathepsin D function, resulting in lysosomal abnormalities and elevated TDP-43 levels in the mouse brain

Introduction Frontotemporal dementia (FTD) is a leading cause of early-onset neurodegeneration, frequently linked to mutations in the GRN gene, which encodes the protein progranulin (PGRN). PGRN is known to play a crucial role in lysosomal function, and its deficiency contributes to FTD pathogenesis. Here, we examined the consequences of PGRN loss on lysosomal homeostasis, focusing on the lysosomal protease cathepsin D (CTSD) and TAR DNA-binding protein 43 (TDP-43) aggregation, hallmarks of FTD and related neurodegenerative diseases. Methods Using mouse models with homozygous and heterozygous GRN deletions and double knockouts for GRN and CTSD , we assessed lysosomal function, CTSD expression and activity, lysosomal-associated membrane protein (LAMP) levels and localization, TDP-43 aggregation, and survival. Results PGRN deficiency resulted in significant alterations in lysosomal function. Despite significantly elevated levels of mature and immature CTSD in PGRN-deficient mice, enzymatic activity was significantly reduced. PGRN deficiency also caused accumulation of lysosomal-associated membrane protein (LAMP) and perinuclear clustering of LAMP1-positive lysosomes, suggestive of disrupted lysosomal trafficking. Correspondingly, insoluble TDP-43 levels significantly increased, implicating lysosomal impairment in defective protein degradation and aggregation. Remarkably, double-knockout mice lacking both PGRN and CTSD exhibited significantly shortened lifespans, highlighting a potential functional interaction between these proteins in maintaining neuronal health and longevity. Discussion These findings underscore the importance of PGRN as a central regulator of lysosomal function and protein homeostasis. Together, the data provide mechanistic insight into PGRN-dependent lysosomal biology and identify pathways that may contribute to GRN -associated FTD and other neurodegenerative disorders.