Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology

Abstract

Prosaposin (PSAP) and progranulin (PGRN) are two lysosomal proteins that interact and modulate the metabolism of lipids, particularly sphingolipids. Alterations in sphingolipid metabolism have been found in schizophrenia. Genetic associations of PSAP and PGRN with schizophrenia have been reported. To further clarify the role of PSAP and PGRN in schizophrenia, we examined PSAP and PGRN levels in postmortem cingulate cortex tissue from healthy controls along with patients who had suffered from schizophrenia, bipolar disorder, or major depressive disorder. We found that PSAP and PGRN levels are reduced specifically in schizophrenia patients. To understand the role of PSAP in the cingulate cortex, we used an AAV strategy to knock down PSAP in neurons located in this region. Neuronal PSAP knockdown led to the downregulation of neuronal PGRN levels and behavioral abnormalities. Cingulate-PSAP-deficient mice exhibited increased anxiety-like behavior and impaired prepulse inhibition, as well as intact locomotion, working memory, and a depression-like state. The behavioral changes were accompanied by increased early growth response protein 1 (EGR-1) and activity-dependent cytoskeleton-associated protein (ARC) levels in the sensorimotor cortex and hippocampus, regions implicated in circuitry dysfunction in schizophrenia. In conclusion, PSAP and PGRN downregulation in the cingulate cortex is associated with schizophrenia pathophysiology.

The roles of prosaposin in neurological disorders: current understandings and prospects

“…Mice with prosaposin knockout in the anterior cingulate cortex exhibited elevated anxiety-like behavior and impaired sensorimotor gating, which are manifestations of schizophrenia. Moreover, the absence of prosaposin in mouse brains leads to an upregulation of early gene expressions associated with schizophrenia, including Early growth response protein 1 (EGR-1) along with the activity-dependent cytoskeleton-associated protein (ARC) (He, Zhang, Flais, & Svenningsson, 2022). This suggests an important role of prosaposin in schizophrenia pathophysiology, but the specific mechanisms and clinical significance require further investigations.…”