The protective role of prosaposin and its receptors in the nervous system

Abstract

Prosaposin (also known as SGP-1) is an intriguing multifunctional protein that plays roles both intracellularly, as a regulator of lysosomal enzyme function, and extracellularly, as a secreted factor with neuroprotective and glioprotective effects. Following secretion, prosaposin can undergo endocytosis via an interaction with the low-density lipoprotein-related receptor 1 (LRP1). The ability of secreted prosaposin to promote protective effects in the nervous system is known to involve activation of G proteins, and the orphan G protein-coupled receptors GPR37 and GPR37L1 have recently been shown to mediate signaling induced by both prosaposin and a fragment of prosaposin known as prosaptide. In this review, we describe recent advances in our understanding of prosaposin, its receptors and their importance in the nervous system.

Keywords: GPCR; Lysosome; Myelination; Nerve; Neuroprotection; Neurotrophic.

Figure 1. Prosaposin and the prosaptides

The region of saposin C that is known to mediate the cytoprotective actions of prosaposin is indicated. The various prosaptides that have been devised to mimic this region are shown in the lower part of the figure. “X” in these sequences denotes D-alanine, and all of the amino acids in the retro-inverso D5 sequence are D-amino acids.

Figure 2. Cell surface receptors for prosaposin

Secreted prosaposin (“PSAP”) can initiate intracellular signaling via binding to GPR37 and GPR37L1. Uptake of prosaposin from the extracellular space can be mediated by LRP1.

Figure 3. Theoretical model of prosaposin function

Prosaposin can be secreted from various cell types in response to cellular stress. Following its release into the extracellular space, prosaposin binds to receptors on nearby neurons and glia to become endocytosed or initiate pro-survival signaling pathways.