The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6

Abstract

Ablation of the cellular prion protein PrPC leads to a chronic demyelinating polyneuropathy (CDP) affecting Schwann cells. Neuron-restricted PrPC expression prevents the disease1, suggesting that it acts in trans through an unidentified Schwann cell receptor. We found that the cAMP concentration in PrPC-deficient sciatic nerves is reduced, suggesting the involvement of a G protein-coupled receptor (GPCR). The amino-terminal “flexible tail” (FT, residues 23-120) of PrPC triggered a concentration-dependent cAMP increase in primary Schwann cells, in the Schwann-cell line SW10, and in Hek293T cells overexpressing the GPCR Gpr126/Adgrg6. In contrast, naïve HEK293T cells and HEK293T cells expressing several other GPCRs did not react to the FT, and ablation of Gpr126 from SW10 cells abolished the FT-induced cAMP response. The FT contains a polycationic cluster (KKRPKPG) similar to the GPRGKPG motif of the Gpr126 agonist, type-IV collagen2 (Col4). A KKRPKPG-containing PrPC-derived peptide (FT23-50) sufficed to induce a Gpr126-dependent cAMP response in cells and mice, and improved myelination in hypomorphic Gpr126 zebrafish mutants. Substitution of the cationic residues with alanines abolished the biological activity of both FT23-50 and the respective Col4 peptide. We conclude that PrPC promotes myelin homeostasis through FT-mediated Gpr126 agonism. Besides clarifying the physiological role of PrPC, these observations are relevant to the pathogenesis of demyelinating polyneuropathies, common debilitating diseases with limited therapeutic options.

Extended characterization of the novel co-isogenic C57BL/6J Prnp−/− mouse line

“…This study confirms the co-isogenicity of the Prnp ZH3/ZH3 line with the C57BL/6J reference strain and its resistance to prion infection. Together with the extensive genomic, transcriptomic and phenotypic characterization reported [2,3], this study corroborates the notion the Prnp ZH3/ZH3 line is a rigorous genetic resource for investigating the role of PrP C in physiology and disease.…”

“…Genetic and phenotypic characterization of this line excluded the presence of artefactual phenotypes reported in non-co-isogenic Prnp -/-mouse lines and confirmed the crucial involvement of PrP C in peripheral myelin maintenance through the interaction with Gpr126 [2,3]. Here, we aimed at extending the characterization of the Prnp ZH3/ZH3 mouse line.…”

Unwrapping the unappreciated: recent progress in Remak Schwann cell biology

“…Another example of a shared molecule between myelinating SCs and RSCs is the G protein-coupled receptor Gpr126/Adgrg6, which controls radial sorting, myelination, remyelination after injury, and long-term SC-axon interactions via several binding partners [23–29]. Gpr126 may also be required in RSCs, as Gpr126 deletion from embryonic SCs resulted in naked small caliber axons in adults [25].…”

G Protein-Coupled Receptors in Myelinating Glia

“…In humans, mutations in LAMA2 , encoding the α2 chain of Laminin-211, cause merosin-deficient congenital muscular dystrophy (MDC1A) with dysmyelination [26-28], suggesting that modulation of GPR126/ADGRG6 might be efficacious in these patients. Intriguingly, a third binding partner for Gpr126/Adgrg6 in Schwann cells has also been described: axonally-derived Prion protein (PrP c ) [29]. Whereas infectious prions consist of a misfolded form of a normal protein called PrP c , the natural functions of PrP c are not fully understood.…”