| Title: |
Mutant prion proteins increase calcium permeability of AMPA receptors, exacerbating excitotoxicity. |
| Authors: |
Ghirardini, Elsa1 (AUTHOR), Restelli, Elena2 (AUTHOR), Morini, Raffaella1 (AUTHOR), Bertani, Ilaria2 (AUTHOR), Ortolan, Davide2 (AUTHOR), Perrucci, Fabio1 (AUTHOR), Pozzi, Davide1 (AUTHOR), Matteoli, Michela1,3 (AUTHOR) michela.matteoli@hunimed.eu, Chiesa, Roberto2 (AUTHOR) michela.matteoli@hunimed.eu |
| Source: |
PLoS Pathogens. 7/16/2020, Vol. 16 Issue 7, p1-26. 26p. |
| Subject Terms: |
*AMPA receptors, *MUTANT proteins, *PRION diseases, *BRAIN degeneration, *CREUTZFELDT-Jakob disease, *GENETIC disorders, *BOVINE spongiform encephalopathy, *ORGANELLES |
| Abstract: |
Prion protein (PrP) mutations are linked to genetic prion diseases, a class of phenotypically heterogeneous neurodegenerative disorders with invariably fatal outcome. How mutant PrP triggers neurodegeneration is not known. Synaptic dysfunction precedes neuronal loss but it is not clear whether, and through which mechanisms, disruption of synaptic activity ultimately leads to neuronal death. Here we show that mutant PrP impairs the secretory trafficking of AMPA receptors (AMPARs). Specifically, intracellular retention of the GluA2 subunit results in synaptic exposure of GluA2-lacking, calcium-permeable AMPARs, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Mutant PrPs linked to different genetic prion diseases affect AMPAR trafficking and function in different ways. Our findings identify AMPARs as pathogenic targets in genetic prion diseases, and support the involvement of excitotoxicity in neurodegeneration. They also suggest a mechanistic explanation for how different mutant PrPs may cause distinct disease phenotypes. Author summary: Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease, fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome. How mutant PrP causes neuronal death and how different mutants encode distinct disease phenotypes is not known. Here we show that mutant PrP alters the subunit composition of glutamate AMPA receptors, promoting cell surface exposure of GluA2-lacking, calcium-permeable receptors, ultimately increasing neuronal vulnerability to excitotoxic cell death. We also demonstrate that the underlying molecular mechanism is the formation of a GluA2 subunit-PrP complex which is retained in the neuronal secretory pathway. PrP mutants associated with clinically different genetic prion diseases have distinct effects on GluA2 trafficking, depending on their tendency to misfold and aggregate in different intracellular organelles, indicating a possible contribution of this mechanism to the disease phenotype. [ABSTRACT FROM AUTHOR] |
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