Batalha VL

Coelho JE

Ferreira DG

Lopes LV

Marques-Morgado I

Miranda HV

Outeiro TF

Rhee JS

Schmitz M

Szego EM

Temido-Ferreira M

Vaz SH

Zerr I

Synucleinopathies, such as Parkinson\u27s 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

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α-synuclein interacts with PrP<sup>C</sup> to induce cognitive impairment through mGluR5 and NMDAR2B

α-synuclein interacts with PrP<sup>C</sup> to induce cognitive impairment through mGluR5 and NMDAR2B

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