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

Anna Henzi; Assunta Senatore; Asvin K K Lakkaraju; Claudia Scheckel; Jonas Mühle; Regina Reimann; Silvia Sorce; Gebhard Schertler; Klaus V Toyka; Adriano Aguzzi

doi:10.1371/journal.pone.0242137

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

PLoS One. 2020 Nov 12;15(11):e0242137. doi: 10.1371/journal.pone.0242137. eCollection 2020.

Affiliations

¹ Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
² Department of Biology and Chemistry, Paul Scherrer Institute, Villingen PSI, Switzerland.
³ Department of Neurology, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Demyelinating Diseases / drug therapy*
Demyelinating Diseases / genetics
Female
Immunoglobulin Fc Fragments / chemistry
Immunoglobulin Fc Fragments / genetics
Male
Mice
Mice, Inbred C57BL
Peptide Fragments / chemistry
Peptide Fragments / genetics
Peptide Fragments / therapeutic use*
Prion Proteins / chemistry*
Prion Proteins / genetics
Receptors, G-Protein-Coupled / agonists*
Recombinant Proteins / chemistry
Recombinant Proteins / pharmacology
Recombinant Proteins / therapeutic use
Sciatic Nerve / metabolism
Transcriptome

Substances

Gpr126 protein, mouse
Immunoglobulin Fc Fragments
Peptide Fragments
Prion Proteins
Receptors, G-Protein-Coupled
Recombinant Proteins

Grants and funding

AH is the recipient of an MD PhD fellowship from Swiss National Foundation (project number 323530_171140). AA is the recipient of an Advanced Grant of the European Research Council, the Nomis Foundation and SystemsX.ch. AS and AKKL are recipients of grants from the Synapsis Foundation. KVT is the recipient of a senior professorship research grant by the University of Würzburg. AA and GS are the recipients of the Swiss National Foundation Sinergia grant CRSII5 183563. Swiss National Foundation: http://www.snf.ch/en/funding/Pages/default.aspx. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.