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Molecular characterization of an aggregation-prone variant of alpha-synuclein used to model synucleinopathies

Lookup NU author(s): Professor Tiago OuteiroORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2019 Elsevier B.V. The misfolding and aggregation of alpha-synuclein (aSyn) are thought to be central events in synucleinopathies. The physiological function of aSyn has been related to vesicle binding and trafficking, but the precise molecular mechanisms leading to aSyn pathogenicity are still obscure. In cell models, aSyn does not readily aggregate, even upon overexpression. Therefore, cellular models that enable the study of aSyn aggregation are essential tools for our understanding of the molecular mechanisms that govern such processes. Here, we investigated the structural features of SynT, an artificial variant of aSyn that has been widely used as a model of aggregation in mammalian cell systems, since it is more prone to aggregation than aSyn. Using Nuclear Magnetic Resonance (NMR) spectroscopy we performed a detailed structural characterization of SynT through a systematic comparison with normal, unmodified aSyn. Interestingly, we found that the conformations adopted by SynT resemble those described for the unmodified protein, demonstrating the usefulness of SynT as a model for aSyn aggregation. However, subtle differences were observed at the N-terminal region involving transient intra and/or intermolecular interactions that are known to regulate aSyn aggregation. Importantly, our results indicate that disturbances in the N-terminal region of SynT, and the consequent decrease in membrane binding of the modified protein, might contribute to the observed aggregation behavior of aSyn, and validate the use of SynT, one of the few models of aSyn aggregation in cultured cells.

Publication metadata

Author(s): Masaracchia C, Konig A, Valiente-Gabioud AA, Peralta P, Favretto F, Strohaker T, Lazaro DF, Zweckstetter M, Fernandez CO, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Year: 2020

Volume: 1868

Issue: 1

Print publication date: 01/01/2020

Online publication date: 30/10/2019

Acceptance date: 08/10/2019

Date deposited: 07/01/2020

ISSN (print): 1570-9639

ISSN (electronic): 1878-1454

Publisher: Elsevier BV


DOI: 10.1016/j.bbapap.2019.140298


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