Progranulin (PGRN) insufficiency is known as a cause of age-related neurodegenerative diseases in human. Haploinsufficiency of PGRN causes frontotemporal lobar degeneration (FTLD), which is characterized by ubiquitinated cytoplasmic inclusions containing TAR DNA binding protein 43 (TDP-43). PGRN deficiency resulting from a homozygous mutation in the GRN gene causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. On the other hand, we have suggested that PGRN is involved in modulating lysosomal function. Therefore, lysosomal function and pathological changes of the brain with aging were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice in the present study.
CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL) were increased in aged PGRN-deficient mice. Immunoreactivity for Lamp1 and expression of lysosome-related genes in the VPM/VPL were also increased in aged PGRN-deficient mice. Aggregates of p62 were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. The TDP-43 aggregates colocalized with p62 in the cytoplasm were also observed in the VPM/VPL of aged PGRN-deficient mice. The expression of glial cell-derived cytotoxic factors was increased in the thalamus of aged PGRN-deficient mice, and neuronal loss was observed only in the VPM/VPL of aged PGRN-deficient mice. In addition, lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.
These results suggest that lysosomal dysfunction in aged PGRN-deficient mice is involved in increased neuroinflammation, TDP-43 aggregation in the cytoplasm of neurons, and NCL-like pathophysiology. Further studies are needed to elucidate how PGRN prevents lysosomal dysfunction with aging.