Toxic effects of amyloid fibrils on cell membranes: the importance of ganglioside GM1
Authors: Bucciantini M., Nosi D., Forzan M., Russo E., Calamai M., Pieri L., Formigli L., Quercioli F., Soria S., Pavone FS., Savistchenko J., Melki R., Stefani M.
Autors Affiliation: Laboratoire d\’Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique, Gif sur Yvette cedex, France; Department of Biochemical Sciences and Research Centre on the molecular basis of Neurodegeneration, University of Florence, Florence, Italy; Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy; Department of Animal Pathology Food Prophylaxis and Hygiene, University of Pisa, Pisa, Italy; LENS – European Laboratory for Non-Linear Spectroscopy, University of Florence, Florence, Italy; National Institute of Optics, CNR Florence Research Area, Florence, Italy; Institute of Applied Physics \”Nello Carrara\”, CNR Florence Research Area, Florence, Italy
Abstract: The interaction of amyloid aggregates with the cell plasma membrane is currently considered among the basic mechanisms of neuronal dysfunction in amyloid neurodegeneration. We used amyloid oligomers and fibrils grown from the yeast prion Sup35p, responsible for the specific prion trait [PSI+], to investigate how membrane lipids modulate fibril interaction with the membranes of cultured H-END cells and cytotoxicity. Sup35p shares no homology with endogenous mammalian polypeptide chains. Thus, the generic toxicity of amyloids and the molecular events underlying cell degeneration can be investigated without interference with analogous polypeptides encoded by the cell genome. Sup35 fibrils bound to the cell membrane without increasing its permeability to Ca2+. Fibril binding resulted in structural reorganization and aggregation of membrane rafts, with GM1 clustering and alteration of its mobility. Sup35 fibril binding was affected by GM1 or its sialic acid moiety, but not by cholesterol membrane content, with complete inhibition after treatment with fumonisin B1 or neuraminidase. Finally, cell impairment resulted from caspase-8 activation after Fas receptor translocation on fibril binding to the plasmamembrane. Our observations suggest that amyloid fibrils induce abnormal accumulation and overstabilization of raft domains in the cell membrane and provide a reasonable, although not unique, mechanistic and molecular explanation for fibril toxicity.
Journal/Review: FASEB JOURNAL
Volume: 26 (2) Pages from: 818 to: 831
More Information: This work was supported by grants from the Ente Cassa di Risparmio di Firenze, the Agence Nationale de la Recherche (ANR-06-BLAN-0266 and ANR08-PCVI-0022-02), the European Community\’s Seventh Framework Programme (FP7/2007-2013) under grant agreement PIEF-GA-2009-254791, the Human Frontier and the EraNet Neuron (Miprotran) programs, and the Centre National de la Recherche Scientifique.KeyWords: amyloid; calcium ion; caspase 8; cholesterol; Fas antigen; fumonisin B1; ganglioside GM1; membrane lipid; oligomer; polypeptide; prion protein; sialic acid; sialidase, animal cell; apoptosis; article; calcium transport; cell degeneration; cell membrane; cell membrane permeability; controlled study; cytotoxicity; diffusion; enzyme activation; fluorescence lifetime imaging microscopy; fluorescence microscopy; fluorescence resonance energy transfer; immunolocalization; lipid raft; membrane binding; membrane damage; membrane structure; mouse; nonhuman; priority journal; protein aggregation; protein binding; protein interaction; sequence homology, Amyloid; Animals; Apoptosis; Cell Line; Cell Membrane; Fluorescence Resonance Energy Transfer; G(M1) Ganglioside; Immunohistochemistry; Membrane Microdomains; Mice; N-Acetylneuraminic Acid; Peptide Termination Factors; Protein Multimerization; Receptors, Death Domain; Saccharomyces cerevisiae Proteins, MammaliaDOI: 10.1096/fj.11-189381Citations: 70data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2020-05-31References taken from IsiWeb of Knowledge: (subscribers only)Connecting to view paper tab on IsiWeb: Click hereConnecting to view citations from IsiWeb: Click here