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α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

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.

Publication metadata

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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