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

作者：Ferreira Diana G; Temido Ferreira Mariana; Miranda Hugo Vicente; Batalha Vania L; Coelho Joana E; Szego Eva M; Marques Morgado Ines; Vaz Sandra H; Rhee Jeong Seop; Schmitz Matthias; Zerr Inga; Lopes Luisa V^*; Outeiro Tiago F^*

来源：Nature Neuroscience, 2017, 20(11): 1569-+.

DOI：10.1038/nn.4648

Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of alpha-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.

• 出版日期2017-11
• 单位河北医科大学