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

Genetic prion diseases are rare, 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 accumulates in the central nervous system of affected individuals and kills neurons through an unknown mechanism. Evidence is emerging that neuronal loss in inherited prion diseases is preceded and possibly caused by synaptic dysfunctions. However, the ultimate link between synaptic dysfunction and neurodegeneration is yet to be found. We previously demonstrated that mutant PrP is retained in the endoplasmic reticulum where it interacts with the alpha2delta subunits of voltage-gated calcium channels. This impairs the correct delivery of the channel complex to the cell surface, impacting synaptic transmission (Senatore et al., Neuron 2012). Nevertheless, this phenomenon alone does not account for neurodegeneration. It has been shown that PrPC engages functional interactions with other proteins that are important for synaptic function such as glutamate receptors. We hypothesize that intracellular retention of mutant PrP may also alter the trafficking of glutamate receptors, thereby producing adverse effects on neuronal function and survival. We started to address this possibility by carrying out biochemical and morphological analyses, electrophysiological recordings and functional imaging in neurons from transgenic mouse models of genetic prion diseases. We found that mutant PrP impairs the membrane delivery of specific AMPA and NMDA receptor subunits. This is associated to a reduction in dendritic spines and basal glutamatergic transmission. 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. 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