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Nat Neurosci. 2017 Nov;20(11):1569-1579. doi: 10.1038/nn.4648. Epub 2017 Sep 25.

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

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Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.
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.
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.
CEDOC, Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
Max Planck Institute for Experimental Medicine, Göttingen, Germany.
Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany.


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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