Loss of GPR37 Increases Susceptibility to Demyelination

GPR37 is an orphan G protein‐coupled receptor that is highly expressed in the brain. Previous work has shown that GPR37 is a receptor for the secreted neuroprotective and glioprotective factor prosaposin and that prosaposin acts through GPR37 to protect cultured astrocytes from oxidative stress‐induced cell death (Meyer et al., Proc. Natl. Acad. USA, 2013). Furthermore, it has previously been shown that prosaposin enhances the survival of oligodendroglia in vitro and also promotes myelination in vivo (Hiraiwa et al., Proc. Natl. Acad. Sci. USA, 1997; Hiraiwa et al., Glia, 1999). Interestingly, several reports indicate that GPR37 is expressed at particularly high levels in oligodendrocytes (Imai et al., Cell, 2001; Cahoy et al., J. Neurosci., 2008). However, despite the aforementioned evidence for GPR37 expression in oligodendroglia, the role(s) that GPR37 may play in oligodendroglial biology remain uncharacterized. Here we show that GPR37‐knockout (GPR37‐KO) mice display more rapid and extensive demyelination than their wild type (WT) counterparts in the cuprizone model of demyelination. Furthermore, we observed that GPR37‐KO mice do not show an increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. Parallel studies on primary cultures of oligodendrocytes also revealed a protective role for GPR37. From these data, we conclude that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, independent of effects on oligodendrocyte proliferation or differentiation. The present work identifies GPR37 as a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis. Ongoing studies in this area seek to elucidate the signaling pathways downstream of GPR37 that regulate oligodendrocyte physiology and support myelination. Support or Funding Information This research was supported through the Fast Forward program of the National Multiple Sclerosis Society.