Inhibition of Group-I Metabotropic Glutamate Receptors Protects Against Prion Toxicity

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2017 Nov 28

PMID 29176838

Citations 28

Authors

Despoina Goniotaki

Asvin K K Lakkaraju

Amulya N Shrivastava

Pamela Bakirci

Silvia Sorce

Assunta Senatore

Rajlakshmi Marpakwar

Simone Hornemann

Fabrizio Gasparini

Antoine Triller

Adriano Aguzzi

Affiliations

Soon will be listed here.

Abstract

Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), 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-PrPC 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.

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