Beta Amyloid Peptide: Research Paper : Unraveling the NaCl Concentration Effect on the First Stages of α-Synuclein Aggregation

Unraveling the NaCl Concentration Effect on the First Stages of α-Synuclein Aggregation

Abstract

Intraneuronal aggregation of the intrinsically disordered protein α-synuclein is at the core of Parkinson's disease and related neurodegenerative disorders. Several reports show that the concentration of salts in the medium heavily affects its aggregation rate and fibril morphology, but a characterization of the individual monomeric conformations underlying these effects is still lacking. In this work, we have applied our α-synuclein-optimized coarse-grained molecular dynamics approach to decipher the structural features of the protein monomer under a range of NaCl concentrations (0.0-1.0 M). The results show that key intramolecular contacts between the terminal domains are lost at intermediate concentrations (leading to extended conformations likely to fibrillate), but recovered at high concentrations (leading to compact conformations likely to evolve toward amorphous aggregates). The pattern of direct interactions of the terminal α-synuclein domains with Na+ and Cl- ions plays a key role in explaining this effect. Our results are consistent with a recent study reporting a fibrillation enhancement at moderate NaCl concentrations but an inhibition at higher concentrations. The present work will contribute to improving our understanding of the structural features of monomeric α-synuclein, determining its NaCl-induced fibrillation propensity and the molecular basis of synucleinopathies, necessary for the future development of disease-halting therapies.

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