title: The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6.
abstract: Ablation of the cellular prion protein PrP(C) leads to a chronic demyelinating polyneuropathy affecting Schwann cells. Neuron-restricted expression of PrP(C) prevents the disease, suggesting that PrP(C) acts in trans through an unidentified Schwann cell receptor. Here we show that the cAMP concentration in sciatic nerves from PrP(C)-deficient mice is reduced, suggesting that PrP(C) acts via a G protein-coupled receptor (GPCR). The amino-terminal flexible tail (residues 23-120) of PrP(C) triggered a concentration-dependent increase in cAMP in primary Schwann cells, in the Schwann cell line SW10, and in HEK293T cells overexpressing the GPCR Adgrg6 (also known as Gpr126). By contrast, naive HEK293T cells and HEK293T cells expressing several other GPCRs did not react to the flexible tail, and ablation of Gpr126 from SW10 cells abolished the flexible tail-induced cAMP response. The flexible tail contains a polycationic cluster (KKRPKPG) similar to the GPRGKPG motif of the Gpr126 agonist type-IV collagen. A KKRPKPG-containing PrPC-derived peptide (FT(23-50)) sufficed to induce a Gpr126-dependent cAMP response in cells and mice, and improved myelination in hypomorphic gpr126 mutant zebrafish (Danio rerio). Substitution of the cationic residues with alanines abolished the biological activity of both FT(23-50) and the equivalent type-IV collagen peptide. We conclude that PrP(C) promotes myelin homeostasis through flexible tail-mediated Gpr126 agonism. As well as clarifying the physiological role of PrP(C), these observations are relevant to the pathogenesis of demyelinating polyneuropathies--common debilitating diseases for which there are limited therapeutic options.
authors: Alexander
authors: A
authors: Küffer
authors: Asvin K K
authors: AK
authors: Lakkaraju
authors: Amit
authors: A
authors: Mogha
authors: Sarah C
authors: SC
authors: Petersen
authors: Kristina
authors: K
authors: Airich
authors: Cédric
authors: C
authors: Doucerain
authors: Rajlakshmi
authors: R
authors: Marpakwar
authors: Pamela
authors: P
authors: Bakirci
authors: Assunta
authors: A
authors: Senatore
authors: Arnaud
authors: A
authors: Monnard
authors: Carmen
authors: C
authors: Schiavi
authors: Mario
authors: M
authors: Nuvolone
authors: Bianka
authors: B
authors: Grosshans
authors: Simone
authors: S
authors: Hornemann
authors: Frederic
authors: F
authors: Bassilana
authors: Kelly R
authors: KR
authors: Monk
authors: Adriano
authors: A
authors: Aguzzi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D024141:Collagen Type IV / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003711:Demyelinating Diseases / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D018583:Pliability; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D024141:Collagen Type IV; C550767:Gpr126 protein, mouse; D008024:Ligands; D010446:Peptide Fragments; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; C543742:stx7l protein, zebrafish; D000242:Cyclic AMP