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Lookup NU author(s): Professor Tiago OuteiroORCiD
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Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of α-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrP C) as a key mediator in aSyn-induced synaptic impairment. The aSyn-associated impairment of long-term potentiation was blocked in Prnp null mice and rescued following PrP C blockade. We found that extracellular aSyn oligomers formed a complex with PrP C that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrP C and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis. Blockade of mGluR5-evoked phosphorylation of NMDAR in aSyn transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.
Author(s): Ferreira DG, Temido-Ferreira M, Miranda HV, Batalha VL, Coelho JE, Szego EM, Marques-Morgado I, Vaz SH, Rhee JS, Schmitz M, Zerr I, Lopes LV, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Nature Neuroscience
Year: 2017
Volume: 20
Issue: 11
Pages: 1569-1579
Online publication date: 25/09/2017
Acceptance date: 21/08/2017
ISSN (print): 1097-6256
ISSN (electronic): 1546-1726
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/nn.4648
DOI: 10.1038/nn.4648
PubMed id: 28945221
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