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.
Jo
E
E
Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada. euijung.jo@utoronto.ca
McLaurin
J
J
Yip
C M
CM
St George-Hyslop
P
P
Fraser
P E
PE
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