Prosaposin, a neurotrophic factor, protects neurons against kainic acid-induced neurotoxicity.

Abstract

Prosaposin (PS) is the precursor of four sphingolipid activator proteins, saposin A-D. PS is both a precursor protein and a neuroprotective factor, and is up-regulated in response to excitotoxicity induced by kainic acid (KA), a glutamate analogue. Excess glutamate release induces neuropathological disorders such as ischemia and seizure. Our group's research revealed that PS immunoreactivity (IR) increased significantly in the hippocampal and cortical neurons on day 3 after KA injection, and high PS levels were maintained even after 3weeks. The increase in PS, but not saposins, as detected by immunoblotting, suggests that the increase in PS-IR after KA injection was not caused by an increase in saposins acting as lysosomal enzymes after neuronal damage but, rather, by an increase in PS as a neurotrophic factor to improve neuronal survival. An 18-mer peptide (PS18) derived from the PS neurotrophic region significantly protected hippocampal neurons against KA-induced destruction. Furthermore, parvalbumin-positive GABAergic inhibitory interneurons and their axons exhibited intense PS expression. These results suggest that axonally transported PS protects damaged hippocampal pyramidal neurons from KA-induced neurotoxicity. Further in vitro studies that include the transfection of the PS gene will help with clarifying the mechanisms underlying the transport and secretion of PS.