Decreased Water Mobility Contributes To Increased α‐Synuclein Aggregation**

Abstract

The solvation shell is essential for the folding and function of proteins, but how it contributes to protein misfolding and aggregation has still to be elucidated. We show that the mobility of solvation shell H 2 O molecules influences the aggregation rate of the amyloid protein α-synuclein (αSyn), a protein associated with Parkinson's disease. When the mobility of H 2 O within the solvation shell is reduced by the presence of NaCl, αSyn aggregation rate increases. Conversely, in the presence CsI the mobility of the solvation shell is increased and αSyn aggregation is reduced. Changing the solvent from H 2 O to D 2 O leads to increased aggregation rates, indicating a solvent driven effect. We show the increased aggregation rate is not directly due to a change in the structural conformations of αSyn, it is also influenced by a reduction in both the H 2 O mobility and αSyn mobility. We propose that reduced mobility of αSyn contributes to increased aggregation by promoting intermolecular interactions.

Water dynamics in eutectic solutions of sodium chloride and magnesium sulfate: implications for life in Europa's subsurface ocean and ice shell

“…A recent study demonstrates that water dynamics independent of dissolved ions play a crucial role in biomolecular self-assembly processes such as pathological protein aggregation. 45 In this regard, the NMR-based approach utilized in this study represents a powerful approach to quantify the mobility of water molecules and ions in biomolecular mixtures, thereby helping to disentangle the complex effect of ions on biological processes. Besides, the NMR-based quantification of water and ion dynamics can be used in various applications such as improving properties of hydrogels as drug delivery systems, 46 optimizing membranes used for water purification and desalination, 47 and developing optimal conditions for microfluidic devices.…”

Oligomer-assisted self-assembly of bisurea in organic solvent media

“…Recently, it has been reported that the presence of NaCl can substantially slow down the dynamics of water molecules in the solvation shell region that, in turn, greatly promotes the site-sensitive aggregation of amyloid protein a-synuclein (a-Syn) that is closely linked with Parkinson's disease. 21 This phenomenon, while representing a different type of molecular cooling yet with similar consequences, motivates the following analysis of the solvent dynamics in the shell region encompassing the bisurea filament.…”

D2O as an Imperfect Replacement for H2O: Problem or Opportunity for Protein Research?

“…A similar enhancement of oligomer stability in heavy water was suggested for transthyretin tetramer . Interestingly, it was recently found that the fibrillization of alpha-synuclein (the protein responsible for Parkinson’s disease) proceeds faster in D 2 O than in water . This acceleration was attributed to enhanced protein–protein interactions in D 2 O that facilitate the refolding of alpha-synuclein, which is required for initiating its fibrillization.…”

“…49 Interestingly, it was recently found that the fibrillization of alpha-synuclein (the protein responsible for Parkinson's disease) proceeds faster in D 2 O than in water. 40 This acceleration was attributed to enhanced protein−protein interactions in D 2 O that facilitate the refolding of alphasynuclein, which is required for initiating its fibrillization. Surprisingly, not only protein-assembly kinetics but even the viscoelastic properties of biopolymer networks can be different in D 2 O and H 2 O.…”

“…While the effect of H/D substitution on kinetics is well established, it is often (implicitly) assumed that the effect of H 2 O/D 2 O substitution on the structure of biomolecules and biomolecular assemblies is small. However, although the use of isotopic substitution in spectroscopic experiments has been mostly successful, there is ample evidence that replacing H 2 O with D 2 O can alter the thermodynamic and structural properties of proteins − and even the formation process and structure of protein assemblies. ,,,− The fact that H 2 O/D 2 O replacement can change the structure of biopolymers and their assemblies should not come as a complete surprise: the hydrogen-bond structures of H 2 O and D 2 O are known to be different, and hydration and the hydrophobic effect are essential for all biomacromolecules, ranging from polysaccharides to proteins. Hydrating water molecules create a water network around solutes that not only acts as structure stabilizer but also mediates intra- and intermolecular interactions.…”