Prosaposin PS18 reduces dopaminergic neurodegeneration in a 6- hydroxydopamine rat model of Parkinson’s disease

Abstract

Abstract Saposin and its precursor prosaposin are endogenous proteins with neurotrophic and anti-apoptotic properties. Prosaposin or its analog prosaposin-derived 18-mer peptide (PS18) reduced neuronal damage in hippocampus and apoptosis in stroke brain, suggesting that prosaposin is neuroprotective in non-dopaminergic cells. Its role in Parkinson’s disease (PD) has not been well characterized. This study aimed to examine the physiological role of PS18 in 6-hydroxydopamine (6-OHDA) cellular and animal models of PD. We found that PS18 significantly antagonized 6-OHDA -mediated dopaminergic neuronal loss and TUNEL in rat primary dopaminergic neuronal culture. The expression and protective effect of prosaposin were examined in unilaterally 6-OHDA -lesioned rats. Administration of 6-OHDA to striatum transiently upregulated the expression of prosaposin in striatum on D3 (day 3) and returned below the basal level on D29. The 6-OHDA -lesioned rats developed bradykinesia and an increase in methamphetamine-mediated rotation. 6-OHDA significantly upregulated the expression of PERK, ATF6, CHOP, and BiP in the lesioned nigra while reducing dopamine transporter DAT mRNA in the lesioned striatum. Pretreatment with PS18 significantly antagonized these responses. Taken together, our data support that PS18 is neuroprotective in cellular and animal models of PD.