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Mov Disord. 2018 Nov;33(11):1675-1684. doi: 10.1002/mds.27478. Epub 2018 Nov 13.

Sensing α-Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration.

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Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
CEDOC, Chronic Diseases Research Center, NOVA Medical School | Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal.
Max Planck Institute for Experimental Medicine, Göttingen, Germany.
Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne, UK.


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.


Parkinson's disease; prion; receptor; spreading; synucleinopathy; α-synuclein


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