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

PLoS Pathogens

Simone Hornemann¹  Fabrizio Gasparini¹  Assunta Senatore¹  Despoina Goniotaki¹  Silvia Sorce¹  Asvin K. K. Lakkaraju¹  Rajlakshmi Marpakwar¹  Antoine Triller²  Pamela Bakirci³  Amulya N. Shrivastava⁴  Adriano Aguzzi⁴ 

[1] Institute of Neuropathology, University of Zurich, Zurich, Switzerland;Novartis Institutes for BioMedical Research, Basel, Switzerland;Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France;École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France

关键词: Prion diseases;    Toxicity;    Immunoprecipitation;    Mouse models;    Neuronal dendrites;    Neurons;    Morphometry;    Glutamate;   

DOI  :  10.1371/journal.ppat.1006733

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY