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

Diana G. Ferreira, Mariana Temido-Ferreira, Hugo Vicente Miranda, Vânia L. Batalha, Joana E. Coelho, Éva M. Szegö, Inês Marques-Morgado, Sandra H. Vaz, Jeong Seop Rhee, Matthias Schmitz, Inga Zerr, Luísa V. Lopes, Tiago F. Outeiro

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1569-1579
Number of pages11
JournalNature Neuroscience
Volume20
Issue number11
DOIs
Publication statusPublished - 1 Jan 2017

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