Journal Article

DZNE-2020-05905

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B.

Ferreira, D. G. ; Temido-Ferreira, M. ; Vicente Miranda, H. ; Batalha, V. L. ; Coelho, J. E. ; Szegö, É. M. ; Marques-Morgado, I. ; Vaz, S. H. ; Rhee, J. S. ; Schmitz, M.DZNE* ; Zerr, I.DZNE* ; Lopes, L. V. (Corresponding author) ; Outeiro, T. F.

2017
Nature Publ. Group58142 London

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Please use a persistent id in citations: doi:10.1038/nn.4648

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 (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.

Keyword(s): Animals (MeSH) ; Cells, Cultured (MeSH) ; Cognitive Dysfunction: metabolism (MeSH) ; Cognitive Dysfunction: pathology (MeSH) ; Excitatory Postsynaptic Potentials: physiology (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: pathology (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Inbred DBA (MeSH) ; Mice, Transgenic (MeSH) ; PrPC Proteins: metabolism (MeSH) ; Protein Binding: physiology (MeSH) ; Rats (MeSH) ; Rats, Sprague-Dawley (MeSH) ; Receptor, Metabotropic Glutamate 5: metabolism (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; NR2B NMDA receptor ; PrPC Proteins ; Receptor, Metabotropic Glutamate 5 ; Receptors, N-Methyl-D-Aspartate ; SNCA protein, human ; alpha-Synuclein

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Contributing Institute(s):

1. Translational Studies and Biomarkers (AG Zerr)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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