Cellular prion protein neither binds to alpha-synuclein oligomers nor mediates their detrimental effects

alpha-Synuclein oligomers are crucial players in the pathogenesis of Parkinson's disease. Some mechanisms involved in -synuclein oligomer detrimental effects include membrane damage, neuroinflammation and protein-protein interactions. Recently, the cellular prion protein (PrPC) emerged as an interactor of -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 -synuclein oligomers and PrPC. In vitro, we assessed -synuclein oligomer toxicity by comparing the effect in Prnp(+/+) versus PrPC knockout (Prnp(0/0)) hippocampal neurons. Through an in vivo acute mouse model, where -synuclein oligomers injected intracerebroventricularly induce memory impairment and neuroinflammation, we verified whether these detrimental effects were preserved in Prnp(0/0) mice. In addition, PrPC--synuclein oligomer direct binding was investigated through surface plasmon resonance. We found that PrPC was not mandatory to mediate -synuclein oligomer detrimental effects in vitro or in vivo. Indeed, -synuclein oligomer toxicity was comparable in Prnp(+/+) and Prnp(0/0) neurons and both Prnp(+/+) and Prnp(0/0) mice injected with -synuclein oligomers displayed memory deficit and hippocampal gliosis. Moreover, surface plasmon resonance analyses ruled out PrPC--synuclein oligomer binding. Our findings indicate that PrPC neither binds -synuclein oligomers nor mediates their detrimental actions. Therefore, it is likely that PrPC-dependent and PrPC-independent pathways co-exist in Parkinson's disease.