Open AccessSoluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice
Author(s) -
Anna Henzi,
Assunta Senatore,
Asvin KK Lakkaraju,
Claudia Scheckel,
Jonas Mühle,
Regina Reimann,
Silvia Sorce,
Gebhard F. X. Schertler,
Klaus V. Toyka,
Adriano Aguzzi
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0242137
Subject(s) - myelin basic protein , peripheral nervous system , receptor , activator (genetics) , sciatic nerve , transcriptome , in vivo , myelin , microbiology and biotechnology , downregulation and upregulation , knockout mouse , biology , in vitro , fusion protein , immunology , chemistry , central nervous system , gene expression , gene , neuroscience , biochemistry , anatomy , genetics , recombinant dna
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 2 Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT 2 Fc 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.