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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Cholesterol differentially regulates α-synuclein binding across membrane packing regimes.
Orianna H Kou1, Brian H Kim2, David H Johnson2
1Department of Physics and Astronomy, University of Southern California, Los Angeles, California, 90089, United States.
Biorxiv : the Preprint Server for Biology
|June 5, 2026
Summary
Cholesterol
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Alpha-synuclein (αSyn) is intrinsically disordered and binds to anionic membranes.
- Cholesterol's role in modulating αSyn-membrane interactions is debated, with conflicting reports of enhancement and suppression.
- Understanding these interactions is crucial given αSyn's association with Parkinson's disease.
Purpose of the Study:
- To investigate how cholesterol's effect on αSyn binding is influenced by the membrane's physical state.
- To reconcile conflicting findings in the literature regarding cholesterol's impact on αSyn-membrane interactions.
Main Methods:
- Utilized a quantitative fluorescence microscopy-based binding assay.
- Measured αSyn binding to reconstituted phosphatidylcholine/phosphatidylserine membranes with varying cholesterol content, lipid tail chemistry, and vesicle curvature.
- Systematically altered membrane packing states to assess cholesterol's influence.
Main Results:
- Cholesterol's effect on αSyn binding is dependent on the membrane's lipid packing state.
- In defect-rich membranes, cholesterol reduced binding by tightening lipid packing.
- In intermediate-defect membranes, cholesterol enhanced binding; tightly packed membranes showed less sensitivity, except at high curvature.
Conclusions:
- Cholesterol does not universally promote or inhibit αSyn binding.
- Cholesterol modulates αSyn-membrane interactions via a packing-regime-dependent mechanism.
- Membrane physical state, influenced by lipid composition and curvature, is a key determinant of cholesterol's regulatory role.
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