Multiple Sclerosis treatment drug, Fingolimod, modulates membrane fusion events in model lipid membranes

JESSICA VALDIVIA PÉREZ; MARIA LAURA FANANI

Córdoba

Congreso; LI reunión Anual de la Sociedad Argentina de Biofísic; 2023

SOCIEDADA ARGENTINA DE BIOFÍSICA

Fingolimod (FTY720) is a drug approved for its use as an oral treatment for MultipleSclerosis (MS), a neurodegenerative disease with an estimated global prevalence of 2.8million. We focus on recently emerging evidence of an alternative mechanism of action ofFingolimod that describes a direct relationship with cell membrane fusion events. Therecent literature on the effect of Fingolimod on membranes is based on studies of synapticvesicle fusion extracted from acidophilic sea urchin cells. This complex model system hasyielded conflicting data regarding the direct action of Fingolimod on vesicle fusion in thepresence and absence of Ca2+, so we propose a study in a simpler and more controlledmodel system.We developed a model of lipid liposome fusion induced by Ca2+ addition and evaluatedits modulation by the presence of Fingolimod. The fusion events were studied by FRET(Forster Resonance Energy Transfer), and dynamic light scattering (DLS). We furtherinvestigated their ability to directly affect membrane surface electrostatics afterspontaneous incorporation with surface potential measurements on monolayers and Zpotential on liposomes.Our results show that the presence of 10 mol% Fingolimod in liposomes decreases theoccurrence of calcium-mediated fusion that could be related to a modulation ofmembrane curvature. This highlights the occurrence of a scarcely-studied modulation ofthe membrane's physical properties by incorporation of an amphiphilic drug, opening anew perspective on the manipulation of membrane-modulated cellular processes.