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

Masaracchia, C., König, A., Valiente-Gabioud, A. A., Peralta, P., Favretto, F., Strohäker, T., et al. (2020). Molecular characterization of an aggregation-prone variant of alpha-synuclein used to model synucleinopathies. Biochimica et Biophysica Acta-Proteins and Proteomics, 1868(1): 140298. doi:10.1016/j.bbapap.2019.140298.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-F8DA-F Version Permalink: http://hdl.handle.net/21.11116/0000-0005-4A0C-C
Genre: Journal Article

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Masaracchia, C., Author
König, A., Author
Valiente-Gabioud, A. A., Author
Peralta, P., Author
Favretto, F., Author
Strohäker, T., Author
Lázaro, D. F., Author
Zweckstetter, M.1, Author              
Fernandez, C. O., Author
Outeiro, T. F., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Alpha-synuclein; Misfolding; Neurodegeneration; Parkinson's disease; Protein aggregation
 Abstract: 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.

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Language(s): eng - English
 Dates: 2019-10-292020-01
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.bbapap.2019.140298
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Title: Biochimica et Biophysica Acta-Proteins and Proteomics
Source Genre: Journal
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Publ. Info: Amsterdam : Elsevier
Pages: 9 Volume / Issue: 1868 (1) Sequence Number: 140298 Start / End Page: - Identifier: ISSN: 1570-9639
CoNE: https://pure.mpg.de/cone/journals/resource/954926938702_5