Decreased Water Mobility Contributes To Increased α-Synuclein Aggregation

Area of Science:

• Biochemistry
• Biophysics
• Neuroscience

Background:

• The solvation shell is crucial for protein folding and function.
• The role of solvation shell dynamics in protein misfolding and aggregation remains unclear.
• Alpha-synuclein (αSyn) aggregation is linked to Parkinson's disease.

Purpose of the Study:

• To investigate the influence of solvation shell water molecule mobility on alpha-synuclein aggregation.
• To determine the effect of different salts and solvents on αSyn aggregation rates.
• To elucidate the mechanisms by which solvent mobility affects αSyn aggregation.

Main Methods:

• Studied the aggregation rate of αSyn under varying solvent conditions (H2O, D2O) and salt concentrations (NaCl, CsI).
• Measured the mobility of solvation shell water molecules and αSyn.
• Analyzed αSyn structural conformations.

Main Results:

• Reduced water mobility in the solvation shell, induced by NaCl, increased αSyn aggregation rates.
• Increased water mobility, induced by CsI, decreased αSyn aggregation rates.
• Switching to D2O as a solvent also increased aggregation rates, indicating a solvent-driven effect.
• Increased aggregation correlated with reduced mobility of both water and αSyn, not solely with conformational changes.

Conclusions:

• Solvation shell water mobility is a critical factor influencing αSyn aggregation.
• Reduced mobility of both solvent and protein promotes intermolecular interactions and aggregation.
• These findings offer new insights into the mechanisms of protein misfolding in neurodegenerative diseases like Parkinson's.