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

doi:10.1038/nn.4648

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

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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 language	English
Pages (from-to)	1569-1579
Number of pages	11
Journal	Nature Neuroscience
Volume	20
Issue number	11
DOIs	https://doi.org/10.1038/nn.4648
Publication status	Published - 1 Jan 2017

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Ferreira, D. G., Temido-Ferreira, M., Miranda, H. V., Batalha, V. L., Coelho, J. E., Szegö, É. M., Marques-Morgado, I., Vaz, S. H., Rhee, J. S., Schmitz, M., Zerr, I., Lopes, L. V., & Outeiro, T. F. (2017). α-synuclein interacts with PrP C to induce cognitive impairment through mGluR5 and NMDAR2B. Nature Neuroscience, 20(11), 1569-1579. https://doi.org/10.1038/nn.4648

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title = "α-synuclein interacts with PrP C to induce cognitive impairment through mGluR5 and NMDAR2B",

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.",

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AU - Batalha, Vânia L.

AU - Coelho, Joana E.

AU - Szegö, Éva M.

AU - Marques-Morgado, Inês

AU - Vaz, Sandra H.

AU - Rhee, Jeong Seop

AU - Schmitz, Matthias

AU - Zerr, Inga

AU - Lopes, Luísa V.

AU - Outeiro, Tiago F.

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N2 - 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.

AB - 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.

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

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