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


Autoři: Elsa Ghirardini aff001;  Elena Restelli aff002;  Raffaella Morini aff001;  Ilaria Bertani aff002;  Davide Ortolan aff002;  Fabio Perrucci aff001;  Davide Pozzi aff001;  Michela Matteoli aff001;  Roberto Chiesa aff002
Působiště autorů: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano—Milan, Italy aff001;  Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy aff002;  Consiglio Nazionale delle Ricerche Institute of Neuroscience, Milan, Italy aff003
Vyšlo v časopise: Mutant prion proteins increase calcium permeability of AMPA receptors, exacerbating excitotoxicity. PLoS Pathog 16(7): e1008654. doi:10.1371/journal.ppat.1008654
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008654

Souhrn

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.

Klíčová slova:

Cell membranes – Genetics of disease – HeLa cells – Neuronal death – Neuronal dendrites – Neurons – Prion diseases – Fatal familial insomnia


Zdroje

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