α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. 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 bod...
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| creator | Ferreira, Diana Temido Ferreira, Mariana Vicente Miranda, Hugo Batalha, Vânia Coelho, Joana Szegö, Éva M Marques-Morgado, Inês Henriques Vaz, Sandra Cristina Rhee, Jeong Seop Schmitz, Matthias Zerr, Inga Lopes, Luisa Outeiro, Tiago |
| description | © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
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.
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. 10.12.2.165), 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. |
| doi_str_mv | 10.1038/nn.4648 |
| format | Article |
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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.
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. 10.12.2.165), 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.</description><identifier>ISSN: 1097-6256</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/nn.4648</identifier><language>eng</language><publisher>New York: Springer Nature</publisher><subject>14/19 ; 631/378/2591/2592 ; 64/110 ; 692/699/375 ; 82 ; 9/30 ; 96 ; 96/1 ; Animal Genetics and Genomics ; Behavioral Sciences ; Biological Techniques ; Biomedicine ; Neurobiology ; Neurosciences</subject><ispartof>Nature neuroscience, 2017-11, Vol.20 (11), p.1569-1579</ispartof><rights>Springer Nature America, Inc. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c209t-94df270b0e0513542bc56cbe65ddabcfee5ac3b922ee0963c33174a6ab5314593</cites><orcidid>0000-0003-3053-2772 ; 0000-0001-8065-9259 ; 0000-0002-8072-613X ; 0000-0003-4258-9397 ; 0000-0002-4356-547X ; 0000-0001-6657-1111 ; 0000-0002-3964-6197 ; 0000-0001-8367-3005 ; 0000-0003-1679-1727</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nn.4648$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nn.4648$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids></links><search><creatorcontrib>Ferreira, Diana</creatorcontrib><creatorcontrib>Temido Ferreira, Mariana</creatorcontrib><creatorcontrib>Vicente Miranda, Hugo</creatorcontrib><creatorcontrib>Batalha, Vânia</creatorcontrib><creatorcontrib>Coelho, Joana</creatorcontrib><creatorcontrib>Szegö, Éva M</creatorcontrib><creatorcontrib>Marques-Morgado, Inês</creatorcontrib><creatorcontrib>Henriques Vaz, Sandra Cristina</creatorcontrib><creatorcontrib>Rhee, Jeong Seop</creatorcontrib><creatorcontrib>Schmitz, Matthias</creatorcontrib><creatorcontrib>Zerr, Inga</creatorcontrib><creatorcontrib>Lopes, Luisa</creatorcontrib><creatorcontrib>Outeiro, Tiago</creatorcontrib><title>α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><description>© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
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.
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. 10.12.2.165), 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.</description><subject>14/19</subject><subject>631/378/2591/2592</subject><subject>64/110</subject><subject>692/699/375</subject><subject>82</subject><subject>9/30</subject><subject>96</subject><subject>96/1</subject><subject>Animal Genetics and Genomics</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedicine</subject><subject>Neurobiology</subject><subject>Neurosciences</subject><issn>1097-6256</issn><issn>1546-1726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpt0MtKAzEUBuBBFKwXfIW40s3U3KdZ1nqFekF04yZkMqdtykymJhnFx_JFfCanVHDj6hwOHz-cP8uOCB4SzEZn3g-55KOtbEAElzkpqNzud6yKXFIhd7O9GJcY40KM1CB7_f7K46fvbA3OI-cTBGNTRB8uLdBjeJyg1PbnqrOAbDv3Lrl3QK5ZGRca8AmlRWi7-QI113X3JJDxFbq_uxg_0fODbGdm6giHv3M_e7m6fJ7c5NOH69vJeJpbilXKFa9mtMAlBiwIE5yWVkhbghRVZUo7AxDGslJRCoCVZJYxUnAjTSkY4UKx_ex0k7sK7VsHMenGRQt1bTy0XdRE8T6fjQra05MNtaGNMcBMr4JrTPjUBOt1e9p7vW7vLzT2ws8h6GXbBd__8Q893tBgjVnpAO8uJrN2XBAtBFOY_QAPUnqn</recordid><startdate>20171101</startdate><enddate>20171101</enddate><creator>Ferreira, Diana</creator><creator>Temido Ferreira, Mariana</creator><creator>Vicente Miranda, Hugo</creator><creator>Batalha, Vânia</creator><creator>Coelho, Joana</creator><creator>Szegö, Éva M</creator><creator>Marques-Morgado, Inês</creator><creator>Henriques Vaz, Sandra Cristina</creator><creator>Rhee, Jeong Seop</creator><creator>Schmitz, Matthias</creator><creator>Zerr, Inga</creator><creator>Lopes, Luisa</creator><creator>Outeiro, Tiago</creator><general>Springer Nature</general><general>Nature Publishing Group US</general><scope>RCLKO</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3053-2772</orcidid><orcidid>https://orcid.org/0000-0001-8065-9259</orcidid><orcidid>https://orcid.org/0000-0002-8072-613X</orcidid><orcidid>https://orcid.org/0000-0003-4258-9397</orcidid><orcidid>https://orcid.org/0000-0002-4356-547X</orcidid><orcidid>https://orcid.org/0000-0001-6657-1111</orcidid><orcidid>https://orcid.org/0000-0002-3964-6197</orcidid><orcidid>https://orcid.org/0000-0001-8367-3005</orcidid><orcidid>https://orcid.org/0000-0003-1679-1727</orcidid></search><sort><creationdate>20171101</creationdate><title>α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B</title><author>Ferreira, Diana ; 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All rights reserved.
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.
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. 10.12.2.165), 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.</abstract><cop>New York</cop><pub>Springer Nature</pub><doi>10.1038/nn.4648</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-3053-2772</orcidid><orcidid>https://orcid.org/0000-0001-8065-9259</orcidid><orcidid>https://orcid.org/0000-0002-8072-613X</orcidid><orcidid>https://orcid.org/0000-0003-4258-9397</orcidid><orcidid>https://orcid.org/0000-0002-4356-547X</orcidid><orcidid>https://orcid.org/0000-0001-6657-1111</orcidid><orcidid>https://orcid.org/0000-0002-3964-6197</orcidid><orcidid>https://orcid.org/0000-0001-8367-3005</orcidid><orcidid>https://orcid.org/0000-0003-1679-1727</orcidid><oa>free_for_read</oa></addata></record> |
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| title | α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B |
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