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  Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity

Carija, A., Pinheiro, F., Pujols, J., Brás, I. C., Fernandes Lázaro, D., Santambrogio, C., et al. (2019). Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity. Redox Biology, 22: 101135. doi:10.1016/j.redox.2019.101135.

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Other : Biasing the native alpha-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity

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 Creators:
Carija, Anita, Author
Pinheiro, Francisca, Author
Pujols, Jordi, Author
Brás, Inês C., Author
Fernandes Lázaro, Diana, Author
Santambrogio, Carlo, Author
Grandori, Rita, Author
Outeiro, Tiago F.1, Author           
Navarro, Susanna, Author
Ventura, Salvador, Author
Affiliations:
1Experimental Neurodegeneration, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_3398149              

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Free keywords: α-synuclein; Disulfide bond; Amyloid; Protein aggregation; Parkinon's disease
 Abstract: The aggregation of α-synuclein (α-syn) into amyloid fibrils is a major pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. The mechanisms underlying the structural transition of soluble and innocuous α-syn to aggregated neurotoxic forms remains largely unknown. The disordered nature of α-syn has hampered the use of structure-based protein engineering approaches to elucidate the molecular determinants of this transition. The recent 3D structure of a pathogenic α-syn fibril provides a template for this kind of studies. The structure supports the NAC domain being a critical element in fibril formation, since it constitutes the core of the fibril, delineating a Greek-key motif. Here, we stapled the ends of this motif with a designed disulfide bond and evaluated its impact on the conformation, aggregation and toxicity of α-syn in different environments. The new covalent link biases the native structural ensemble of α-syn toward compact conformations, reducing the population of fully unfolded species. This conformational bias results in a strongly reduced fibril formation propensity both in the absence and in the presence of lipids and impedes the formation of neurotoxic oligomers. Our study does not support the Greek-key motif being already imprinted in early α-syn assemblies, discarding it as a druggable interface to prevent the initiation of fibrillation. In contrast, it suggests the stabilization of native, compact ensembles as a potential therapeutic strategy to avoid the formation of toxic species and to target the early stages of PD.

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Language(s): eng - English
 Dates: 2019-02-042019-02-052019-04
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.redox.2019.101135
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Project name : This work was funded by the Spanish Ministry of Economy and Competitiveness (BIO2016-783-78310-R) to S.V., by ICREA, ICREA-Academia 2015 to S.V. and by Fundación La Marato de TV3 (Ref. 20144330) to S.V. and to SV and TFO. TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) and by DFG SFB 1286 (project B8).
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Title: Redox Biology
Source Genre: Journal
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Publ. Info: Amsterdam [u.a.] : Elsevier
Pages: - Volume / Issue: 22 Sequence Number: 101135 Start / End Page: - Identifier: ISSN: 2213-2317
CoNE: https://pure.mpg.de/cone/journals/resource/2213-2317