Mutant prion proteins increase calcium permeability of AMPA receptors, exacerbating excitotoxicity

PLoS Pathogens
Elsa GhirardiniRoberto Chiesa

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.

References

Dec 1, 1987·Journal of Virology·R J KascsakH Diringer
Oct 13, 1995·The Journal of Biological Chemistry·S Lehmann, D A Harris
Mar 29, 1994·Proceedings of the National Academy of Sciences of the United States of America·L MonariB Ghetti
Dec 10, 1996·Proceedings of the National Academy of Sciences of the United States of America·M VeyS B Prusiner
Dec 1, 1996·Genetic Analysis : Biomolecular Engineering·D R BorcheltD L Price
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·R ChiesaD A Harris
Jun 7, 2000·Neuropathology and Applied Neurobiology·P V BelichenkoJ R Fraser
Aug 31, 2001·The Journal of Biological Chemistry·L IvanovaD A Harris
Jun 14, 2003·Journal of Virology·Roberto ChiesaDavid A Harris
Aug 12, 2003·Cell Calcium·Mark Arundine, Michael Tymianski
Nov 19, 2003·Neuron·Ingo H GregerEdward B Ziff
Jul 2, 2004·Molecular Biology of the Cell·Daniela SarnataroChiara Zurzolo
Jan 6, 2005·The Journal of Biological Chemistry·Luana FioritiRoberto Chiesa
Mar 18, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Corette J WierengaGina G Turrigiano
May 16, 2006·Current Opinion in Neurobiology·Shin Kwak, John H Weiss
Feb 6, 2007·Trends in Neurosciences·Siqiong June Liu, R Suzanne Zukin
Jun 8, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Martin FuhrmannJochen Herms
Nov 9, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ralf KleeneMelitta Schachner
Nov 29, 2007·The Journal of Comparative Neurology·Rita GarbelliCarolina Frassoni
Apr 16, 2008·Molecular and Cellular Neurosciences·Qingming HouHeng-Ye Man
Feb 12, 2009·PloS One·Dorothea RutishauserAdriano Aguzzi
Mar 6, 2009·Cell Adhesion & Migration·Jonathan G Hanley
May 22, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Melanie A GaineyGina G Turrigiano
Feb 13, 2010·The Biochemical Journal·Andy A ColeThomas S Reese
May 18, 2010·Neuron·Karine Pozo, Yukiko Goda
Jul 16, 2010·The Biochemical Journal·Emiliano BiasiniRoberto Chiesa
Aug 19, 2010·Pharmacological Reviews·Stephen F TraynelisRay Dingledine
Nov 10, 2010·PloS One·Elena RestelliRoberto Chiesa
Oct 18, 2012·Nature Communications·Nicole T WattNigel M Hooper
Dec 27, 2013·International Journal of Cell Biology·Assunta SenatoreRoberto Chiesa
Dec 17, 2014·Frontiers in Cellular Neuroscience·Thomas E Chater, Yukiko Goda

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Citations

Feb 4, 2021·The Journal of Physiology·Stuart G Cull-Candy, Mark Farrant
Jul 3, 2021·International Journal of Molecular Sciences·Marco DiociaiutiGiovanna D'Arcangelo

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Methods Mentioned

BETA
transgenic
transfection
confocal microscopy
co-immunoprecipitation
co-IP

Software Mentioned

ASW
- FL
Prism
MetaFluor
GraphPad
ImageJ
Excel
NeuronStudio
VS
JACoP

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