Amyloid Aggregates Alter the Membrane Mobility of GM1 Gangliosides

Abstract

Neuronal dysfunction in neurodegenerative pathologies such as Alzheimer's disease is currently attributed to the interaction of amyloid aggregates with the plasmamembrane. Amongst the variety of toxic mechanisms proposed, one involves the binding of amyloid species to GM1 gangliosides. GM1 takes part into the formation of membrane rafts, specialized microdomains responsible for the compartmentalization of cellular processes such as signalling and protein trafficking. GM1 has antineurotoxic, neuroprotective, and neurorestorative effects on various central neurotransmitter systems. In this study, we investigated the effect of amyloid-like aggregates formed by the yeast prion Sup35 on the membrane mobility of GM1. Although Sup35 is not associated to any disease, it contains a highly amyloidogenic structural motif (Sup35NM) and has been used extensively as a model peptide for studying amyloid aggregation. Preformed Sup35 and Sup35NM aggregates were incubated with neuroblastoma cells and GM1 molecules were subsequently labeled with biotinylated CTX-B and streptavidin quantum dots (QDs). Single QDs bound to GM1 were then tracked. The trajectories of QDs labeled GM1 molecules were used to calculate their mean square displacement (MSD) and extrapolate their diffusion coefficients (D). The diffusion behavior of GM1 in the absence or in the presence of full length Sup35 aggregates was found to be substantially identical. By contrast, the mobility of GM1 decreased dramatically in the presence of Sup35NM aggregates. In this case, the median D of GM1 was found to be approximately one order of magnitude lower. Furthermore, the motion of GM1 appeared to change from mostly Brownian in the absence of the Sup35NM aggregates to mainly confined in their presence. The considerable interference of amyloid-like aggregates with the lateral diffusion of GM1 might imply a consequent loss of function of GM1, thus contributing to explain the toxic mechanism ascribed to this particular interaction.