Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

Abstract

<jats:title>Abstract</jats:title><jats:p>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 (FT<jats:sub>2</jats:sub>Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT<jats:sub>2</jats:sub>Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the peripheral demyelinating neuropathy 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.</jats:p><jats:sec><jats:title>Summary blurb</jats:title><jats:p>A dimeric prion protein ligand activates Adgrg6 but fails to induce pro-myelination signaling upon chronic treatment in a mouse model of peripheral demyelination.</jats:p></jats:sec>

The prion protein is not required for peripheral nerve repair after crush injury

“…We have previously described that Prnp ZH3/ZH3 mice exhibit an early upregulation of repair Schwann cell markers in sciatic nerves, which probably represents an early sign of the peripheral nerve disease (26). In the present study, we confirmed that the 2-3 months old Prnp ZH3/ZH3 mice undergoing crush injury showed a two-fold upregulation of GFAP in their uninjured sciatic nerves when compared to WT mice.…”