GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant

Abstract

Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G>T [Lys349Asp]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in GPR37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

“…However, their patterns of distribution are distinct because the highest levels of GPR37L1 expression are in astrocytes and certain specialized cell types such as the Bergmann glia of the cerebellum (58). The high degree of homology between GPR37 and GPR37L1 suggests that they might share the same ligands, and moreover, KO of either receptor was found to result in increased seizure susceptibility, with genetic deletion of both receptors resulting in an even more dramatic increase in vulnerability to seizures (30). Given our findings that deletion of GPR37 increases damage induced by ischemia and the similar findings recently made for mice lacking GPR37L1 (29), it will be interesting in the future to explore whether loss of both these receptors together might result in even more profound susceptibility to ischemia-induced damage.…”

“…The mouse line was backcrossed with WT C57BL/6J mice (The Jackson Laboratory) for 10 generations each to ensure uniformity of genetic background. Genetic deletion of GPR37 was confirmed by DNA sequencing (30). All mice were maintained on a C57BL/6J background and housed in a 12-h light-dark cycle, with food and water available ad libitum.…”

Glio‐ and neuro‐protection by prosaposin is mediated by orphan G‐protein coupled receptors GPR37L1 and GPR37

“…This could be the reason why the pro-seizure phenotype of double GPR37L1/GPR37 knockout mice is so severe (Giddens et al, 2017). This could be the reason why the pro-seizure phenotype of double GPR37L1/GPR37 knockout mice is so severe (Giddens et al, 2017).…”

“…Neither HEK293 cells nor yeast used in the recent conflicting studies (Coleman et al, 2016;Giddens et al, 2017;Ngo et al, 2017) express GPR37L1 or GPR37 natively, nor were they ever demonstrated to be responsive to PSAP or prosaptides. These cells might not necessarily recapitulate the intracellular environment of astrocytes and neurons which are the natural habitats of GPR37L1 and GPR37.…”

“…Moreover, on the background of their high constitutive activity, TX14(A) was ineffective (Coleman et al, 2016;Giddens et al, 2017;Ngo et al, 2017). Regulation of this constitutive activity was suggested to occur via cleavage of the extracellular part of GPR37L1 (Coleman et al, 2016;Mattila, Tuusa, & Petaja-Repo, 2016).…”