Progranulin Regulations of Lysosomal Homeostasis and Its Involvement in Neurodegenerative Diseases

Abstract

Progranulin (PGRN) haploinsufficiency resulting from the loss-of-function mutations of GRN gene causes frontotemporal lober degeneration characteristic of TDP-43-positive inclusion (FTLD-TDP). The patients with homozygous mutations in the GRN gene present with adult onset neuronal ceroid lipofuscinosis. While the functional role of PGRN regulating neurodegenerative diseases is still controversial, evidences that PGRN regulates lysosomal function and biogenesis are accumulating. We previously demonstrated that PGRN is localized to lysosomes and the expression increases in lysosomal biogenesis. Furthermore, PGRN suppresses exacerbated lysosomal biogenesis especially in activated microglia after traumatic brain injury and with aging in mice, indicating that PGRN composes of negative feedback loop of lysosomal biogenesis. Interestingly, secreted PGRN is incorporated and transported into lysosomes through sortilin or cation-independent mannose 6-phosphate receptor, and facilitated acidification of lysosomes. These findings indicate that PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis through acidification of lysosomes. On the other hand, other groups recently reported that granulin peptides stabilize Cathepsin D and work as a chaperone for beta-glucocerebrosidase. These investigations about PGRN function involved in lysosomes have spotlighted on the pathogenic mechanisms of neurodegenerative diseases especially in FTLD-TDP. The understanding of PGRN trafficking into lysosomes and its regulation of lysosomes could provide a clue of the remedy for currently incurable neurodegenerative diseases.