Fig. 1

Endogenous soluble oligomers are inextricably associated with lipid/vesicle binding. Depicted is an possible explanation for the detection of a soluble αsyn oligomer. In the cytoplasm, αsyn exists in an equilibrium between a disordered slightly compact monomer and membrane-bound α-helix confirmation. The N-terminus of αsyn binds to vesicle membranes via electrostatic interactions and adopts an α-helix structure. αSyn most likely binds to localized areas of vesicle surfaces with lipid-packing defects. Normally, in the cell ~5–10% of αsyn is interacting with vesicle surfaces. The same percentage is also proposed for soluble oligomers. Covalent bonds between adjacent αsyn molecules capture the confirmations bound to the vesicle surface. Covalent modification of amino-acid residue side chains, especially lysine, following chemical crosslinking neutralizes a portion of αsyn charge required for membrane binding. The captured species could then retain the membrane-bound confirmation and enter the aqueous phase for subsequent detection. Thus, endogenous soluble functional oligomers are unlikely, in agreement with several studies. Instead, endogenous oligomers may represent confirmations of membrane-bound αsyn. This hypothesis makes lipid-syn interactions at the membrane a crucial mediator of pathology initiation. DSP dithiobis(succinimidyl propionate), DSG disuccinimidyl glutarate