Polyunsaturated Fatty Acid Modulates Membrane-Bound Monomeric α-Synuclein by Modulating Membrane Microenvironment...

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alpha-synuclein (α-Syn) aggregation is linked to Parkinson's disease and depends on lipid interactions.
• The precise mechanism of fatty acid-mediated regulation of α-Syn remains unclear.

Purpose of the Study:

• To explore the mechanism of fatty acid-dependent regulation of monomeric α-Syn100.
• To investigate the role of docosahexaenoic acid (DHA) in modulating α-Syn100 interaction with synaptic vesicle-like membranes at an atomistic level.

Main Methods:

• Extensive atomistic molecular dynamics simulations.
• Enhanced-sampling techniques.
• Analysis of protein-lipid interactions, membrane structure, and α-Syn100 conformation.

Main Results:

• α-Syn100 binds to membranes via its N-terminal region, with insertion depth and structure modulated by DHA.
• DHA preferentially sorts into the membrane near α-Syn100, altering lipid composition and membrane properties.
• DHA induces β-sheet structures in the α-Syn100 NAC domain, promoting self-assembly and extended conformations.

Conclusions:

• DHA plays a critical role in regulating monomeric α-Syn100 structure and membrane interactions.
• DHA promotes α-Syn100 oligomerization by inducing specific structural changes and facilitating self-assembly.
• These findings provide atomistic insights into DHA's regulatory mechanism, impacting α-Syn100's physiological and pathological functions.