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Protein trapping leads to altered synaptic proteostasis in synucleinopathies

Lookup NU author(s): Professor Tiago OuteiroORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. Parkinson's disease (PD) is associated with the accumulation of alpha-synuclein (aSyn) in intracellular inclusions known as Lewy bodies and Lewy neurites. Under physiological conditions, aSyn is found at the presynaptic terminal and exists in a dynamic equilibrium between soluble, membrane-associated and aggregated forms. Emerging evidence suggests that, under pathological conditions, aSyn begins to accumulate and acquire a toxic function at the synapse, impairing their normal function and connectivity. However, the precise molecular mechanisms linking aSyn accumulation and synaptic dysfunction are still elusive. Here, we provide an overview of our current findings and discuss the hypothesis that certain aSyn aggregates may interact with proteins with whom aSyn normally does not interact with, thereby trapping them and preventing them from performing their normal functions in the cell. We posit that such abnormal interactions start to occur during the prodromal stages of PD, eventually resulting in the overt manifestation of clinical features. Therefore, understanding the nature and behaviour of toxic aSyn species and their contribution to aSyn-mediated toxicity is crucial for the development of therapeutic strategies capable of modifying disease progression in PD and other synucleinopathies.

Publication metadata

Author(s): Santos PI, Outeiro TF

Publication type: Review

Publication status: Published

Journal: FEBS Journal

Year: 2020

Volume: 287

Issue: 24

Pages: 5294-5303

Print publication date: 01/12/2020

Online publication date: 13/05/2020

Acceptance date: 07/05/2020

ISSN (print): 1742-464X

ISSN (electronic): 1742-4658

Publisher: Blackwell Publishing Ltd


DOI: 10.1111/febs.15364

PubMed id: 32400966