Prosaposin Reduces α-Synuclein in Cells and Saposin C Dislodges it from Glucosylceramide-enriched Lipid Membranes

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder affecting over 1% of the 65 + age population. Saposin C, a lysosomal protein required for the normal activity of glucocerebrosidase (GCase), may serve as a disease modifier in PD. Saposin C is cleaved from its precursor, Prosaposin (PSAP), which is secreted as an uncleaved protein and exerts neuroprotective effects. In this study, we aim to elucidate the neuroprotective roles of PSAP and saposin C in PD by evaluating their effects on alpha-synuclein accumulation in human neuroblastoma cells. Stable overexpression of PSAP reduced monomeric alpha-synuclein levels in SH-SY5Y cells, while PSAP knockdown by small interfering RNA led to the opposite effect, and those effects were independent of GCase activity. Autophagy flux was decreased by stable PSAP overexpression. Furthermore, a flow-through assay revealed that recombinant saposin C was able to detach alpha-synuclein from artificial glucosylceramide-enriched lipid membranes at the lysosomal pH. Taken together, our findings provide further evidence that PSAP and saposin C as key proteins involved in alpha-synuclein clearance by dislodging it from lipid membranes.

Automated summary

The study reveals that PSAP and saposin C are involved in the clearance of alpha-synuclein by dislodging it from lipid membranes. These findings are important for a better understanding of the pathogenesis of Parkinson's disease.