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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
A stable lipid-induced aggregate of alpha-synuclein
Malte Drescher1, Bart D van Rooijen, Gertjan Veldhuis
1Department of Molecular Physics, Leiden University, P.O. Box 9504, 2300 RA Leiden, The Netherlands.
Journal of the American Chemical Society
|March 5, 2010
Summary
Parkinson's disease protein alpha-Synuclein (alphaS) forms lipid-induced aggregates with vesicles. These aggregates explain the protein's horseshoe structure and cause membrane leakage, potentially resolving literature discrepancies.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Alpha-Synuclein (alphaS) is intrinsically disordered and implicated in Parkinson's disease.
- Its interaction with membranes is crucial for its function and pathology.
- Understanding alphaS aggregation is key to deciphering its role in neurodegeneration.
Purpose of the Study:
- To investigate the aggregation mechanism of alpha-Synuclein (alphaS) upon interaction with lipid vesicles.
- To elucidate the structural basis of alphaS aggregation and its effect on membrane integrity.
Main Methods:
- Spin-label Electron Paramagnetic Resonance (EPR) spectroscopy.
- Double Electron-Electron Resonance (DEER) to measure intermolecular distances.
- Utilized four single mutants of alphaS to probe aggregate formation.
Main Results:
- Alpha-Synuclein (alphaS) forms well-defined aggregates with POPG SUVs.
- Two distinct dimer structures coexist, with primary interactions in helix 2 (residues 50-100).
- Aggregate formation explains the previously observed horseshoe conformation and induces membrane leakage and size reduction.
Conclusions:
- Lipid-induced alphaS aggregation provides a structural rationale for the horseshoe conformation.
- The observed membrane disruption may explain conflicting findings in previous studies.
- This research offers insights into alphaS pathobiology relevant to Parkinson's disease.
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