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

Alexander Küffer, Asvin K.K. Lakkaraju, Amit Mogha, Sarah C. Petersen, Kristina Airich, Cédric Doucerain, Rajlakshmi Marpakwar, Pamela Bakirci, Assunta Senatore, Arnaud Monnard, Carmen Schiavi, Mario Nuvolone, Bianka Grosshans, Simone Hornemann, Frederic Bassilana, Kelly Monk, Adriano Aguzzi

Research output: Contribution to journalArticle

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Abstract

Ablation of the cellular prion protein PrPC leads to a chronic demyelinating polyneuropathy affecting Schwann cells. Neuron-restricted expression of PrPC prevents the disease, suggesting that PrPC acts in trans through an unidentified Schwann cell receptor. Here we show that the cAMP concentration in sciatic nerves from PrPC -deficient mice is reduced, suggesting that PrPC acts via a G protein-coupled receptor (GPCR). The amino-terminal flexible tail (residues 23-120) of PrPC 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 PrPC promotes myelin homeostasis through flexible tail-mediated Gpr126 agonism. As well as clarifying the physiological role of PrPC, these observations are relevant to the pathogenesis of demyelinating polyneuropathies - common debilitating diseases for which there are limited therapeutic options.

Original languageEnglish (US)
Pages (from-to)464-468
Number of pages5
JournalNature
Volume536
Issue number7617
DOIs
StatePublished - Aug 8 2016
Externally publishedYes

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G-Protein-Coupled Receptors
Schwann Cells
Tail
Ligands
Collagen Type IV
Polyneuropathies
Zebrafish
Peptides
Sciatic Nerve
Myelin Sheath
Alanine
Homeostasis
Prion Proteins
Neurons
Cell Line
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Küffer, A., Lakkaraju, A. K. K., Mogha, A., Petersen, S. C., Airich, K., Doucerain, C., ... Aguzzi, A. (2016). The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature, 536(7617), 464-468. https://doi.org/10.1038/nature19312

The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. / Küffer, Alexander; Lakkaraju, Asvin K.K.; Mogha, Amit; Petersen, Sarah C.; Airich, Kristina; Doucerain, Cédric; Marpakwar, Rajlakshmi; Bakirci, Pamela; Senatore, Assunta; Monnard, Arnaud; Schiavi, Carmen; Nuvolone, Mario; Grosshans, Bianka; Hornemann, Simone; Bassilana, Frederic; Monk, Kelly; Aguzzi, Adriano.

In: Nature, Vol. 536, No. 7617, 08.08.2016, p. 464-468.

Research output: Contribution to journalArticle

Küffer, A, Lakkaraju, AKK, Mogha, A, Petersen, SC, Airich, K, Doucerain, C, Marpakwar, R, Bakirci, P, Senatore, A, Monnard, A, Schiavi, C, Nuvolone, M, Grosshans, B, Hornemann, S, Bassilana, F, Monk, K & Aguzzi, A 2016, 'The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6', Nature, vol. 536, no. 7617, pp. 464-468. https://doi.org/10.1038/nature19312
Küffer A, Lakkaraju AKK, Mogha A, Petersen SC, Airich K, Doucerain C et al. The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature. 2016 Aug 8;536(7617):464-468. https://doi.org/10.1038/nature19312
Küffer, Alexander ; Lakkaraju, Asvin K.K. ; Mogha, Amit ; Petersen, Sarah C. ; Airich, Kristina ; Doucerain, Cédric ; Marpakwar, Rajlakshmi ; Bakirci, Pamela ; Senatore, Assunta ; Monnard, Arnaud ; Schiavi, Carmen ; Nuvolone, Mario ; Grosshans, Bianka ; Hornemann, Simone ; Bassilana, Frederic ; Monk, Kelly ; Aguzzi, Adriano. / The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. In: Nature. 2016 ; Vol. 536, No. 7617. pp. 464-468.
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