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Journal Article

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


Outeiro,  Tiago F.
Experimental Neurodegeneration, Max Planck Institute of Experimental Medicine, Max Planck Society;

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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.

Cite as: https://hdl.handle.net/21.11116/0000-0003-6327-2
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.