Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Brain. 2019 Feb 1;142(2):249-254. doi: 10.1093/brain/awy318.
α-Synuclein oligomers are crucial players in the pathogenesis of Parkinson's disease. Some mechanisms involved in α-synuclein oligomer detrimental effects include membrane damage, neuroinflammation and protein-protein interactions. Recently, the cellular prion protein (PrPC) emerged as an interactor of α-synuclein oligomers, apparently mediating their detrimental activities. Through direct in vivo and in vitro approaches we herein investigated the existence of a direct cross-talk between α-synuclein oligomers and PrPC. In vitro, we assessed α-synuclein oligomer toxicity by comparing the effect in Prnp+/+ versus PrPC knockout (Prnp0/0) hippocampal neurons. Through an in vivo acute mouse model, where α-synuclein oligomers injected intracerebroventricularly induce memory impairment and neuroinflammation, we verified whether these detrimental effects were preserved in Prnp0/0 mice. In addition, PrPC-α-synuclein oligomer direct binding was investigated through surface plasmon resonance. We found that PrPC was not mandatory to mediate α-synuclein oligomer detrimental effects in vitro or in vivo. Indeed, α-synuclein oligomer toxicity was comparable in Prnp+/+ and Prnp0/0 neurons and both Prnp+/+ and Prnp0/0 mice injected with α-synuclein oligomers displayed memory deficit and hippocampal gliosis. Moreover, surface plasmon resonance analyses ruled out PrPC-α-synuclein oligomer binding. Our findings indicate that PrPC neither binds α-synuclein oligomers nor mediates their detrimental actions. Therefore, it is likely that PrPC-dependent and PrPC-independent pathways co-exist in Parkinson's disease.
α-突触核蛋白寡聚体是帕金森病发病机制中的关键因素。α-突触核蛋白寡聚体的一些有害作用机制包括膜损伤、神经炎症和蛋白质-蛋白质相互作用。最近，细胞朊病毒蛋白（PrPC）作为α-突触核蛋白寡聚体的相互作用蛋白出现，显然介导了其有害活性。通过直接的体内和体外方法，我们在此研究了α-突触核蛋白寡聚体和 PrPC 之间是否存在直接的串扰。在体外，我们通过比较 Prnp+/+ 和 PrPC 敲除（Prnp0/0）海马神经元中 α-突触核蛋白寡聚体的效应来评估 α-突触核蛋白寡聚体的毒性。通过急性小鼠模型，我们将 α-突触核蛋白寡聚体脑室内注射，诱导记忆障碍和神经炎症，验证这些有害作用是否在 Prnp0/0 小鼠中保留。此外，我们通过表面等离子体共振研究了 PrPC-α-突触核蛋白寡聚体的直接结合。我们发现 PrPC 不是介导 α-突触核蛋白寡聚体在体内或体外产生有害作用的必需因素。实际上，α-突触核蛋白寡聚体毒性在 Prnp+/+ 和 Prnp0/0 神经元中是相当的，而且注射了α-突触核蛋白寡聚体的 Prnp+/+ 和 Prnp0/0 小鼠都表现出记忆缺陷和海马神经胶质增生。此外，表面等离子体共振分析排除了 PrPC-α-突触核蛋白寡聚体的结合。我们的研究结果表明，PrPC 既不与 α-突触核蛋白寡聚体结合，也不介导其有害作用。因此，在帕金森病中，PrPC 依赖和非依赖途径可能同时存在。
