PUBLICATION
The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6
- Authors
- Küffer, A., Lakkaraju, A.K., Mogha, A., Petersen, S.C., Airich, K., Doucerain, C., Marpakwar, R., Bakirci, P., Senatore, A., Monnard, A., Schiavi, C., Nuvolone, M., Grosshans, B., Hornemann, S., Bassilana, F., Monk, K.R., Aguzzi, A.
- ID
- ZDB-PUB-160809-2
- Date
- 2016
- Source
- Nature 536(7617): 464-8 (Journal)
- Registered Authors
- Mogha, Amit, Monk, Kelly, Petersen, Sarah C.
- Keywords
- Cellular neuroscience, Mechanisms of disease
- MeSH Terms
-
- Amino Acid Sequence
- Receptors, G-Protein-Coupled/agonists*
- Receptors, G-Protein-Coupled/deficiency
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism*
- Female
- Zebrafish/genetics
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Peptide Fragments/chemistry
- Peptide Fragments/pharmacology
- Ligands
- Collagen Type IV/chemistry
- Collagen Type IV/pharmacology
- Molecular Sequence Data
- Pliability
- HEK293 Cells
- Demyelinating Diseases/metabolism
- Homeostasis/drug effects
- Cyclic AMP/metabolism
- Animals
- Schwann Cells/drug effects
- Schwann Cells/metabolism
- Protein Structure, Tertiary
- Myelin Sheath/metabolism
- Humans
- Prion Proteins
- Mice
- Amino Acid Motifs
- Prions/chemistry
- Prions/genetics
- Prions/metabolism*
- Prions/pharmacology*
- Sciatic Nerve/drug effects
- Sciatic Nerve/metabolism
- PubMed
- 27501152 Full text @ Nature
Citation
Küffer, A., Lakkaraju, A.K., Mogha, A., Petersen, S.C., Airich, K., Doucerain, C., Marpakwar, R., Bakirci, P., Senatore, A., Monnard, A., Schiavi, C., Nuvolone, M., Grosshans, B., Hornemann, S., Bassilana, F., Monk, K.R., Aguzzi, A. (2016) The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature. 536(7617):464-8.
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 PrP(C)-derived peptide (FT23-50) 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 FT23-50 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping