Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

• DOI: 10.1371/journal.pone.0242137
• Publication Date: 2020-11-12T18:51:11Z
• Authors: Anna Henzi; Assunta Senatore; Asvin K. K. Lakka...; Claudia Scheckel; Jonas Mühle; Regina Reimann; Silvia Sorce; Gebhard Schertler; Klaus V. Toyka; Adriano Aguzzi
• Keywords: Male; 0301 basic medicine; Science; 10208 Institute of Neuropathology; 610 Medicine & health; Genetics and Molecular Biology; 1100 General Agricultural and Biological Sciences; Prion Proteins; Cell Line; Receptors, G-Protein-Coupled; Mice; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; Animals; 1000 Multidisciplinary; 0303 health sciences; Q; R; General Medicine; Sciatic Nerve; Peptide Fragments; Recombinant Proteins; Immunoglobulin Fc Fragments; 3. Good health; Mice, Inbred C57BL; General Biochemistry; 570 Life sciences; biology; Medicine; Female; General Agricultural and Biological Sciences; Transcriptome; Research Article; Demyelinating Diseases

The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.