Data di Pubblicazione:
2014
Citazione:
The impact of mutant prion protein on synaptic maturation and function / E. Ghirardini, R. Morini, E. Restelli, M. Pozzoli, I. Bertani, R. Chiesa, M. Matteoli. ((Intervento presentato al 9. convegno FENS Forum of Neuroscience tenutosi a Milano nel 2014.
Abstract:
Genetic prion diseases are 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.
Aim
Although evidence is emerging that neuronal loss in inherited prion diseases is preceded by synaptic dysfunctions, the mechanisms at the origin of neurodegeneration are still unclear.
We have recently 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 (Neuron 74:300-313, 2012). Since PrPC has been reported to interact also with AMPA receptors (AMPARs) and other proteins involved in synaptic maturation, we tested whether expression of mutant PrP altered localization and function of the above mentioned proteins, thus disrupting synaptic transmission and leading to enhanced susceptibility to excitotoxic cell death.
Methods
We carried out biochemical and morphological analyses, electrophysiological recordings and functional imaging in neurons expressing mutant PrPs.
Results and Conclusions
Preliminary results showed that mutant PrP affects spine morphology, synaptic transmission and neuronal susceptibility to AMPA toxicity. We found that mutant PrP selectively interacts with AMPAR GluR2 subunit resulting in surface exposure of GluR2-lacking AMPARs, which have increased calcium permeability and altered functional properties. Through this process, mutant PrP may therefore affect neuronal integrity by altering calcium homeostasis, intracellular signaling and synaptic plasticity.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
E. Ghirardini, R. Morini, E. Restelli, M. Pozzoli, I. Bertani, R. Chiesa, M. Matteoli
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