Validation of phosphorylated GPR17 receptors as pharmacological target for the treatment of demyelinating diseases

• Applicant: Dr. Sebastian Fritzwanker
• Subject Area: Pharmacology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572604773

Multiple sclerosis (MS) is a neuroinflammatory disease that begins with the infiltration of immune cells into the CNS, causing inflammation, demyelination and axonal degeneration. Extensive research has focused on identifying novel MS treatments that preserve oligodendrocytes and enhance their remyelination potential. Among these, the orphan G protein-coupled receptor GPR17 has attracted particular attention. GPR17 is a receptor that is transiently expressed in late-stage oligodendrocyte precursor cells (OPCs) and actively differentiating oligodendrocytes, but not in mature myelinating oligodendrocytes. Genetic ablation or pharmacological inhibition of GPR17 in mice accelerates both developmental myelination and remyelination. These results suggest that GPR17 antagonists may promote remyelination in MS and related demyelinating diseases. We have recently developed a new technology that facilitates the visualization of activated GPCRs in their tissue of origin using phosphosite-specific antibodies. In the case of GPR17, we found that it is phosphorylated at the carboxyl-terminal serine351 and threonine356 in an agonist- and GRK-dependent manner. In the developing mouse brain, non-phosphorylated GPR17 receptors are expressed at high density in regions of the white matter where active myelination occurs. Phosphorylation of GPR17 increases dramatically after P20. This apparent mismatch indicates that the expression of the endogenous GPR17 ligand is regulated in spatial and temporal manner during development. In the adult brain, GPR17 receptors are expressed in OPCs, which are distributed throughout the brain. In all adult OPCs, most GPR17 receptors are present in an activated and phosphorylated form. These results suggest that the regulation of GPR17 during oligodendrocyte differentiation is much more complex than originally thought. Therefore, we propose to dissect the mechanisms of GPR17 phosphorylation in vitro and in vivo. We will analyze in detail the ratio of total and phosphorylated GPR17 during development and in mouse models of demyelination and remyelination. Specifically, this proposal aims to 1) characterize the homologous and heterologous phosphorylation of GPR17 in vitro, 2) evaluate the spatio-temporal pattern of GPR17 phosphorylation in the developing mouse brain, 3) characterize the endogenous ligand for GPR17, 4) analyze the pharmacological modulation of GPR17 phosphorylation in ex vivo brain slice cultures, 5) evaluate GPR17 phosphorylation in the cuprizone mouse model of demyelination and remyelination, 6) elucidate the physiological function of GPR17 phosphorylation in transgenic mouse models, and 7) validate phospho-GPR17 immunohistochemistry as a biomarker of oligodendrocyte differentiation in rodent and human brain. The planned work will facilitate the validation of the phosphorylated GPR17 receptor as a pharmacological target for the treatment of demyelinating diseases.

• DFG Programme: Research Grants