Accumulation of prosaposin and progranulin around the subfornical organ induces polydipsia in SAP-D-deficient mice

Prosaposin (PSAP), a precursor of saposins, is essential for lysosomal hydrolysis of sphingolipids. It binds with progranulin (PGRN) and transports from the Golgi to lysosomes, where it is processed into saposins. PSAP is also secreted and functions on various cells, including neurons. We found that PSAP is highly expressed in the subfornical organ (SFO), a thirst center, in SAP-D-deficient (SAP-D^-/-) mice, which develop primary polydipsia. As polyuria progresses, CD68-positive active microglia infiltrate the SFO and strongly express PSAP and PGRN. Lysosomal marker LAMP1 analysis in the SFO of mice with advanced polydipsia showed increased LAMP1 expression and decreased co-localization of PSAP and LAMP1 in microglia and neurons. This suggests that SAP-D-deficient PSAP struggles to reach lysosomes, causing intracellular accumulation. c-Fos-positive cell counts in the SFO remained significantly higher in SAP-D^-/- mice, reflecting altered drinking behavior. These findings imply that PSAP may drive polydipsia progression.