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

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

© 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. © 2018 International Parkinson and Movement Disorder Society.

Publication metadata

Author(s): Bras IC, Lopes LV, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Movement Disorders

Year: 2018

Volume: 33

Issue: 11

Pages: 1675-1684

Online publication date: 13/11/2018

Acceptance date: 26/07/2018

ISSN (print): 0885-3185

ISSN (electronic): 1531-8257

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/mds.27478

DOI: 10.1002/mds.27478

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