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 (PrPC) 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 PrPC blockade. We found that extracellular aSyn oligomers formed a complex with PrPC that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrPC 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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The authors thank L. Gros for figure layout design and C. Fahlbusch (University Medical Center Göttingen), A. Margarida Nascimento and J. Rino (Instituto de Medicina Molecular (iMM) Bioimaging facility), I. Moreira and J. Marques (iMM Rodent facility), and the iMM Histology and Comparative Pathology laboratory for technical assistance. M.T.F., H.V.M. and J.E.C. were supported by individual grants from Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/52228/2013; SFRH/BPD/109347/2015; SFRH/BPD/87647/2012); L.V.L. and T.F.O. were supported by a grant from the Fritz Thyssen Stiftung (Az., Germany. L.V.L. received an iMM Lisboa internal fund (BIG – Breakthrough Idea Grant) for part of the project. L.V.L. is an Investigator FCT, Portugal. T.F.O. is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Germany. LISBOA-01-0145-FEDER-007391, project co-financed by FEDER, POR Lisboa 2020 - Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia.

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Author notes

    • Luísa V Lopes
    •  & Tiago F Outeiro

    These authors jointly directed this work.


  1. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.

    • Diana G Ferreira
    • , Mariana Temido-Ferreira
    • , Hugo Vicente Miranda
    • , Vânia L Batalha
    • , Joana E Coelho
    • , Inês Marques-Morgado
    • , Sandra H Vaz
    •  & Luísa V Lopes
  2. Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

    • Diana G Ferreira
    • , Éva M Szegö
    •  & Tiago F Outeiro
  3. Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.

    • Diana G Ferreira
  4. CEDOC, Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.

    • Hugo Vicente Miranda
    •  & Tiago F Outeiro
  5. Max Planck Institute for Experimental Medicine, Göttingen, Germany.

    • Jeong Seop Rhee
    •  & Tiago F Outeiro
  6. Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany.

    • Matthias Schmitz
    •  & Inga Zerr


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D.G.F. performed most of the experimental work, analyzed data and wrote the manuscript. M.T.-F., J.E.C., V.L.B. and S.H.V. assisted with behavior and calcium experiments. E.M.S. assisted with animal experiments. I.M.-M. performed the immunohistochemistry experiments. M.S., J.S.R. and I.Z. provided the Prnp−/− mice and experimental support. H.V.M. produced and characterized aSyn species. L.V.L. and T.F.O. coordinated the study, designed the experiments and wrote the manuscript. All of the authors approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Luísa V Lopes or Tiago F Outeiro.

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  1. 1.

    aSyn oligomers increase intracellular Ca2+ in neurons

    Initial calcium response of FURA-2 AM loaded wildtype neurons to aSyn oligomers (aSyn mon, 500 nM)

  2. 2.

    aSyn oligomers do not increase intracellular Ca2+ in Prnp (-/-) neurons

    Initial calcium response of FURA-2 AM loaded Prnp (-/-) neurons to aSyn oligomers (aSyn mon, 500 nM)

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