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

Abstract

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 (PrP^C) 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 PrP^C. In vitro, we assessed α-synuclein oligomer toxicity by comparing the effect in Prnp^+/+ versus PrP^C knockout (Prnp^0/0) 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 Prnp^0/0 mice. In addition, PrP^C-α-synuclein oligomer direct binding was investigated through surface plasmon resonance. We found that PrP^C 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 Prnp^0/0 neurons and both Prnp^+/+ and Prnp^0/0 mice injected with α-synuclein oligomers displayed memory deficit and hippocampal gliosis. Moreover, surface plasmon resonance analyses ruled out PrP^C–α-synuclein oligomer binding. Our findings indicate that PrP^C neither binds α-synuclein oligomers nor mediates their detrimental actions. Therefore, it is likely that PrP^C-dependent and PrP^C-independent pathways co-exist in Parkinson's disease.

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