
Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity
Author(s) -
Despoina Goniotaki,
Asvin KK Lakkaraju,
Amulya Nidhi Shrivastava,
Pamela Bakirci,
Silvia Sorce,
Assunta Senatore,
Rajlakshmi Marpakwar,
Simone Hornemann,
F. Gasparini,
Antoine Triller,
Adriano Aguzzi
Publication year - 2017
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006733
Subject(s) - metabotropic glutamate receptor 5 , metabotropic glutamate receptor , metabotropic glutamate receptor 1 , glutamate receptor , neurodegeneration , neurotoxicity , toxicity , metabotropic glutamate receptor 6 , metabotropic receptor , metabotropic glutamate receptor 7 , metabotropic glutamate receptor 4 , pharmacology , biology , receptor , chemistry , medicine , biochemistry , disease , organic chemistry
Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrP C is required for toxicity, suggesting the existence of deleterious PrP C -dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrP C ), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo . We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrP C antibodies in organotypic brain slices. Prion-mimetic antibodies increased mGluR5 clustering around dendritic spines, mimicking the toxicity of Aβ oligomers. Oral treatment with the mGluR5 inhibitor, MPEP, delayed the onset of motor deficits and moderately prolonged survival of prion-infected mice. Although group-I mGluR inhibition was not curative, these results suggest that it may alleviate the neurological dysfunctions induced by prion diseases.