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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.

Author information

1
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.
2
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
3
CEDOC, Chronic Diseases Research Center, NOVA Medical School | Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal.
4
Max Planck Institute for Experimental Medicine, Göttingen, Germany.
5
Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne, UK.

Abstract

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.

KEYWORDS:

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

PMID:
30423195
DOI:
10.1002/mds.27478

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