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

Autor: Joana E. Coelho, Tiago F. Outeiro, Mariana Temido-Ferreira, Inga Zerr, Jeong-Seop Rhee, Matthias Schmitz, Éva M. Szegö, Sandra H. Vaz, Diana G. Ferreira, Vânia L. Batalha, Hugo Vicente Miranda, Luísa V. Lopes, Inês Marques-Morgado
Přispěvatelé: Repositório da Universidade de Lisboa
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
physiology [Excitatory Postsynaptic Potentials]
pathology [Cognitive Dysfunction]
Receptor
Metabotropic Glutamate 5
animal diseases
metabolism [Hippocampus]
Mice
Transgenic
Disease
Receptors
N-Methyl-D-Aspartate
metabolism [PrPC Proteins]
Rats
Sprague-Dawley
metabolism [Cognitive Dysfunction]
Mice
03 medical and health sciences
0302 clinical medicine
ddc:570
mental disorders
Animals
PrPC Proteins
metabolism [alpha-Synuclein]
SNCA protein
human
metabolism [Receptors
N-Methyl-D-Aspartate]
Receptor
Cognitive impairment
Cells
Cultured
Synucleinopathies
Metabotropic glutamate receptor 5
General Neuroscience
NR2B NMDA receptor
Cognition
Rats
nervous system diseases
Mice
Inbred C57BL
pathology [Hippocampus]
030104 developmental biology
Mice
Inbred DBA
alpha-Synuclein
α synuclein
Psychology
metabolism [Receptor
Metabotropic Glutamate 5]
Neuroscience
physiology [Protein Binding]
030217 neurology & neurosurgery
Zdroj: Nature reviews / Neuroscience 20(11), 1569-1579 (2017). doi:10.1038/nn.4648
Nature Neuroscience
ISSN: 1546-1726
1097-6256
Popis: © 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.
Databáze: OpenAIRE
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