Paradoxical Effect of Trehalose on the Aggregation of α-Synuclein: Expedites Onset of Aggregation Yet Reduces Fibril Load

Aggregation of α-synuclein is closely connected to the pathology of Parkinson's disease. The phenomenon involves multiple steps, commenced by partial misfolding and eventually leading to mature amyloid fibril formation. Trehalose, a widely accepted osmolyte, has been shown previously to inhibit aggregation of various globular proteins owing to its ability to prevent the initial unfolding of protein. In this study, we have examined if it behaves in a similar fashion with intrinsically disordered protein α-synuclein and possesses the potential to act as therapeutic agent against Parkinson's disease. It was observed experimentally that samples coincubated with trehalose fibrillate faster compared to the case in its absence. Molecular dynamics simulations suggested that this initial acceleration is manifestation of trehalose's tendency to perturb the conformational transitions between different conformers of monomeric protein. It stabilizes the aggregation prone "extended" conformer of α-synuclein, by binding to its exposed acidic residues of the C terminus. It also favors the β-rich oligomers once formed. Interestingly, the total fibrils formed are still promisingly less since it accelerates the competing pathway toward formation of amorphous aggregates.