Sensing α-synuclein from the outside via the prion protein: implications for neurodegeneration

© 2018 International Parkinson and Movement Disorder Society Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α-synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell-to-cell spreading of α-synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α-synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N-methyl-d-aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α-synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α-synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long-term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α-synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. T.F.O. is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), by SFB1286, and by the European Union's Horizon 2020 research and innovation program under grant agreement 721802 SynDegen. L.V.L. is an investigator FCT, supported by Fundação para a Ciência e Tecnologia (Portugal).