The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation.
The aggregation of alpha-synuclein is believed to be a critical factor in the etiology of Parkinson's disease. alpha-Synuclein is an abundant neuronal protein of unknown function, which is enriched in the presynaptic terminals of neurons. Although alpha-synuclein is found predominantly in the cytosolic fractions, membrane-bound alpha-synuclein has been suggested to play an important role in fibril formation. The effects of alpha-synuclein on lipid bilayers of different compositions were determined using fluorescent environment-specific probes located at various depths. alpha-Synuclein-membrane interactions were found to affect both protein and membrane properties. Our results indicate that in addition to electrostatic interactions, hydrophobic interactions are important in the association of the protein with the bilayer, and lead to disruption of the membrane. The latter was observed by atomic force microscopy and fluorescent dye leakage from vesicles. The kinetics of alpha-synuclein fibril formation were significantly affected by the protein association and subsequent membrane disruption, and reflected the conformation of alpha-synuclein. The ability of alpha-synuclein to disrupt membranes correlated with the binding affinity of alpha-synuclein for the particular membrane composition, and to the induced helical conformation of alpha-synuclein. Protofibrillar or fibrillar alpha-synuclein caused a much more rapid destruction of the membrane than soluble monomeric alpha-synuclein, indicating that protofibrils (oligomers) or fibrils are likely to be significantly neurotoxic.
Zhu
Min
M
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
Li
Jie
J
Fink
Anthony L
AL
D015081:2-Naphthylamine / Q000031:analogs & derivatives*; D005456:Fluorescent Dyes; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007848:Laurates; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D051843:Synucleins; D051844:alpha-Synuclein
D005456:Fluorescent Dyes; D007848:Laurates; D008051:Lipid Bilayers; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D015081:2-Naphthylamine; C065580:laurdan