Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity

• Published in: PLoS pathogens 2017-11, Vol.13 (11), p.e1006733
• Main Authors: Goniotaki, Despoina, Lakkaraju, Asvin K K, Shrivastava, Amulya N, Bakirci, Pamela, Sorce, Silvia, Senatore, Assunta, Marpakwar, Rajlakshmi, Hornemann, Simone, Gasparini, Fabrizio, Triller, Antoine, Aguzzi, Adriano
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - administration & dosage; Biocompatibility; Biology and Life Sciences; Biomedical research; Brain; Brain research; Brain slice preparation; Cascades; Clustering; Creutzfeldt-Jakob disease; Dendritic spines; Female; Funding; Glutamic acid receptors (metabotropic); Humans; Infections; Inhibition; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mimicry; Neurodegeneration; Neurological complications; Neurological diseases; Neurons - drug effects; Neurons - metabolism; Neuropathology; Neurotoxicity; Oligomers; Pathogenesis; Pharmacology; Prion Diseases - drug therapy; Prion Diseases - genetics; Prion Diseases - metabolism; Prion protein; Proteins; PrPC Proteins - genetics; PrPC Proteins - metabolism; PrPC Proteins - toxicity; Pyridines - administration & dosage; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Receptor, Metabotropic Glutamate 5 - genetics; Receptor, Metabotropic Glutamate 5 - metabolism; Receptors; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Research and Analysis Methods; Rodents; Signaling; Supervision; Toxicity
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006733

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.