Developing novel tools to probe the function of GPR37 within the CNS
Lead Research Organisation:
University of Sussex
Department Name: Sch of Life Sciences
Abstract
G-protein coupled receptors (GPCRs) mediate the transmission of extracellular signals into intracellular responses and they are therefore a major target for therapeutic drugs, including those within the central nervous system (CNS). GPR37 is a member of the Class A GPCR family and has been of particular interest since its initial description over 20 years ago based upon its almost exclusive expression within the CNS and its identification as a substrate for the E3 ubiquitin ligase parkin, which is associated with autosomal recessive Parkinson's disease. Moreover, disruptions in dopaminergic neurotransmission in GPR37 knockout mice implicate this receptor as a modulator of dopamine neurons and hence, presumably, Parkinson's disease. Furthermore, mutations in GPR37 have been associated with autism and altered expression occurs in depression and bipolar disorder.
Despite these separate lines of evidence all indicating that GPR37 is a disease-relevant receptor, further examination of functional aspects of this receptor have, until recently, been hampered by its status as an orphan GPCR with an unknown endogenous ligand. However, GPR37 has very recently been "deorphanised" and its endogenous ligand recognised as prosaposin which signals via Gi/Go G-proteins to inhibit cAMP second messenger production. The potential importance of the prosaposin/GPR37 system is further emphasized by the fact that prosaposin deficiency is associated with a fatal and rapidly progressive lysosomal storage disorder in man. Clearly, GPR37 is a potentially highly attractive therapeutic target although at the moment, and given the only very recent deorphanisation of this receptor, there is a lack of tools compounds with which to further explore the function of GPR37. Accordingly, the aim of this proposal is to identify compounds that selectively alter the function of GPR37 and examine the effects of such compounds in cellular and in vivo models relating to neurodegeneration, nerve injury and neuronal survival.
Despite these separate lines of evidence all indicating that GPR37 is a disease-relevant receptor, further examination of functional aspects of this receptor have, until recently, been hampered by its status as an orphan GPCR with an unknown endogenous ligand. However, GPR37 has very recently been "deorphanised" and its endogenous ligand recognised as prosaposin which signals via Gi/Go G-proteins to inhibit cAMP second messenger production. The potential importance of the prosaposin/GPR37 system is further emphasized by the fact that prosaposin deficiency is associated with a fatal and rapidly progressive lysosomal storage disorder in man. Clearly, GPR37 is a potentially highly attractive therapeutic target although at the moment, and given the only very recent deorphanisation of this receptor, there is a lack of tools compounds with which to further explore the function of GPR37. Accordingly, the aim of this proposal is to identify compounds that selectively alter the function of GPR37 and examine the effects of such compounds in cellular and in vivo models relating to neurodegeneration, nerve injury and neuronal survival.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M01715X/1 | 01/11/2015 | 01/09/2018 | |||
| 1661841 | Studentship | BB/M01715X/1 | 01/11/2015 | 31/08/2018 | Rachael Besser |
| Description | A cellular model incorporating the drug target, G-protein coupled receptor GPR37, has been established in house. Assay development is underway using this cell line in order to enable the screening of compounds to identify modulation of the drug target. Discovering tool compounds for the receptor will enable better understanding of the function of GPR37 and hopefully lead to generation of drugs for the treatment of central nervous system disorders. |
| Exploitation Route | Once tool compounds have been identified this will enable validation of GPR37 as a viable drug target for its implicated central nervous system disorders, including Parkinson's disease, autism, bipolar and depressive disorders. This will allow drug discovery schemes to focus on developing drugs which modulate GPR37 for the benefit of pharmaceutical companies, the NHS and the public. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Ongoing research towards the discovery of compounds which have the capacity to treat central nervous system disorders will have a positive economical and societal impact as it will aid the development of drugs for disorders with a clinical unmet need. This will be beneficial to pharmaceutical companies, the NHS and the public. |