GPR37L1 mutation associated with a novel neurological disorder

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 DESCRIPTION (provided by applicant): GPR37L1 is a G protein-coupled receptor that is expressed almost exclusively in the central nervous system. This receptor is highly expressed in astrocytes as well as in oligodendrocytes and certain neuronal populations, and my laboratory recently identified GPR37L1 as a receptor for the secreted neuroprotective and glioprotective factor prosaposin. A GPR37L1 mutation was recently found to be associated with a novel inherited neurological disorder characterized by headaches and seizures starting at the onset of puberty, with the seizures growing more frequent and severe throughout the teen years and ultimately resulting in death by the late teens. The GPR37L1 mutation identified in the affected members of this family is a missense mutation that changes an amino acid in the receptor's third cytoplasmic loop, a region of most G protein-coupled receptors that is important for controlling their signaling and regulation. We will assess the effects of the mutation on the folding, trafficking and signaling of GPR37L1 in order to determine how this mutation might be causing human disease and how patients harboring this mutation might be treated. In addition to providing insights into the neurological disorder associated with the GPR37L1 mutation, these studies will also shed significant light on the normal function of GPR37L1 and thereby set the stage for targeting this receptor pharmacologically in order to generally benefit patients sufferin from stroke and/or other neurodegenerative conditions.