The interaction between mutant prion protein and glutamate receptors: a novel mechanism for neuronal dysfunction in genetic prion diseases

Aims Genetic prion diseases are invariably fatal neurodegenerative disorders linked to mutations in the PRNP gene encoding the cellular prion protein (PrPC). PRNP mutations favor the conformational conversion of PrPC into a pathogenic misfolded isoform that kills neurons through an unknown mechanism. We previously found that intracellular retention of mutant PrP impairs synaptic delivery of voltage-gated calcium channels, leading to alteration in neurotransmission (Senatore et al., Neuron 2012). However, this phenomenon alone does not account for neurodegeneration. There is evidence that PrPC engages functional interactions with other synaptic proteins such as glutamate receptors. We hypothesize that intracellular retention of mutant PrP may alter the trafficking of glutamate receptors, thereby producing adverse effects on neuronal function and survival. Methods We carried out biochemical and morphological analyses, electrophysiological recordings and functional imaging in neurons from transgenic mouse models of genetic prion diseases. Results We found that mutant PrP impairs the membrane delivery of specific AMPA and NMDA receptor subunits, and this is associated to an overall alteration in postsynaptic structure and excitatory neurotransmission. Moreover, retention of the GluA2 subunit of AMPA receptor results in exposure of GluA2-lacking, calcium-permeable AMPA receptors, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Conclusions Our results demonstrate that mutant PrP impairs the trafficking of glutamate receptors, leading to a significant alteration in glutamatergic neurotransmission and increased predisposition to excitotoxicity. These findings identify a new pathological mechanism for genetic prion diseases and may lead to novel therapeutic approaches for such incurable conditions