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.
Highlights
The decisive event in the pathogenesis of prion diseases is the conversion of the normal cellular prion protein (PrPC) into an aggregated conformational variant called PrPSc [1]
Prion diseases are a result of ordered accumulation of the misfolded conformer of cellular prion protein (PrPC), a GPI anchored protein expressed on the cell surface
We have discovered that genetic ablation, or pharmacological inhibition, of group-I metabotropic glutamate receptors is beneficial against prion neurotoxicity in vitro and in vivo
Summary
The decisive event in the pathogenesis of prion diseases is the conversion of the normal cellular prion protein (PrPC) into an aggregated conformational variant called PrPSc [1]. Expression of PrPC at the cell surface is required for the self-propagation of prions, and for mediating the toxicity induced by PrPSc [2], a process that results in endoplasmic reticulum (ER) stress and in impaired protein translation [3]. PrPC has been shown to interact with transmembrane signal-transducing proteins [4] and disturbing these interactions might lead to the neurotoxicity seen in prion diseases [5]. Among the proteins interacting with PrPC are glutamate receptors [6]. Metabotropic glutamate receptors (mGluRs) may play a role in prion diseases. Changes in mGluR1, leading to reduced expression levels of phospholipases, were observed in the cerebral cortex of Creutzfeldt-Jakob disease (CJD) patients [9]. Abnormal mGluR1 signaling correlated with PrPSc deposition, histological changes, and clinical scores [10]
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