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.

中文翻译：

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α-突触核蛋白与PrPC相互作用，通过mGluR5和NMDAR2B诱导认知障碍。

突触核病，如帕金森氏病和路易小体痴呆，是神经退行性疾病，其特征是α-突触核蛋白（aSyn）在称为路易小体的细胞内包裹物中积累。原纤维前可溶性aSyn寡聚物，而不是较大的包裹体，目前被认为是潜在的突触功能障碍的物种。我们确定细胞病毒蛋白（PrP ^C）是aSyn诱导的突触损伤的关键介质。在Prnp缺失小鼠中阻断了aSyn相关的长期增强作用，并在PrP ^C阻断后得以挽救。我们发现细胞外aSyn寡聚物与PrP ^C形成复合物通过代谢型谷氨酸受体5（mGluR5）诱导Fyn激酶的磷酸化。的PrP的ASYN接合^Ç和Fyn激活NMDA受体（NMDAR）和改变钙体内平衡。在aSyn转基因小鼠中，mGluR5引起的NMDAR磷酸化的阻断可挽救突触和认知缺陷，支持以下假设：受体介导的机制独立于孔形成和膜泄漏，足以触发由细胞外aSyn诱导的早期突触损伤。