alpha-Synuclein membrane interactions and lipid specificity.
With the discovery of missense mutations (A53T and A30P) in alpha-synuclein (alpha-Syn) in several families with early onset familial Parkinson's disease, alpha-Syn aggregation and fibril formation have been thought to play a role in the pathogenesis of alpha-synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. As previous reports have suggested that alpha-Syn plays a role in lipid transport and synaptic membrane biogenesis, we investigated whether alpha-Syn binds to a specific lipid ligand using thin layer chromatography overlay and examined the changes in its secondary structure using circular dichroism spectroscopy. alpha-Syn was found to bind to acidic phospholipid vesicles and this binding was significantly augmented by the presence of phosphatidylethanolamine, a neutral phospholipid. We further examined the interaction of alpha-Syn with lipids by in situ atomic force microscopy. The association of soluble wild-type alpha-Syn with planar lipid bilayers resulted in extensive bilayer disruption and the formation of amorphous aggregates and small fibrils. The A53T mutant alpha-Syn disrupted the lipid bilayers in a similar fashion but at a slower rate. These results suggest that alpha-Syn membrane interactions are physiologically important and the lipid composition of the cellular membranes may affect these interactions in vivo.
Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada. euijung.jo@utoronto.ca
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Jo
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McLaurin
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Yip
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St George-Hyslop
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Fraser
D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002855:Chromatography, Thin Layer; D002942:Circular Dichroism; D006801:Humans; D008051:Lipid Bilayers; D050356:Lipid Metabolism; D008297:Male; D018625:Microscopy, Atomic Force; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D051843:Synucleins; D051844:alpha-Synuclein
D008051:Lipid Bilayers; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein