共 29 条
The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6
被引:170
作者:
Kuffer, Alexander
[1
]
Lakkaraju, Asvin K. K.
[1
]
Mogha, Amit
[2
,3
]
Petersen, Sarah C.
[2
,3
]
Airich, Kristina
[1
]
Doucerain, Cedric
[1
]
Marpakwar, Rajlakshmi
[1
]
Bakirci, Pamela
[1
]
Senatore, Assunta
[1
]
Monnard, Arnaud
[1
]
Schiavi, Carmen
[1
]
Nuvolone, Mario
[1
]
Grosshans, Bianka
[4
]
Hornemann, Simone
[1
]
Bassilana, Frederic
[4
]
Monk, Kelly R.
[2
,3
]
Aguzzi, Adriano
[1
]
机构:
[1] Univ Zurich, Inst Neuropathol, CH-8091 Zurich, Switzerland
[2] Washington Univ, Sch Med, Dept Dev Biol, 660 South Euclid Ave,Campus Box 8103, St Louis, MO 63110 USA
[3] Hope Ctr Neurol Disorders, 660 South Euclid Ave,Campus Box 8103, St Louis, MO 63110 USA
[4] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland
来源:
基金:
瑞士国家科学基金会;
欧洲研究理事会;
新加坡国家研究基金会;
关键词:
PERIPHERAL MYELIN MAINTENANCE;
SCHWANN-CELL DEVELOPMENT;
GPR126;
ZEBRAFISH;
APOPTOSIS;
NEURONS;
DOMAIN;
MICE;
RNA;
D O I:
10.1038/nature19312
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Ablation of the cellular prion protein PrPC leads to a chronic demyelinating polyneuropathy affecting Schwann cells. Neuron-restricted expression of PrPC prevents the disease(1), 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(2). 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 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 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.
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页码:464 / +
页数:21
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