Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases.
The conversion of peptides or proteins from their soluble native states into intractable amyloid deposits is associated with a wide range of human disorders. Misfolded protein oligomers formed during the process of aggregation have been identified as the primary pathogenic agents in many such conditions. Here, we show the existence of a quantitative relationship between the degree of binding to neuronal cells of different types of oligomers formed from a model protein, HypF-N, and the GM1 content of the plasma membranes. In addition, remarkably similar behavior is observed for oligomers of the Aβ42 peptide associated with Alzheimer's disease. Further analysis has revealed the existence of a linear correlation between the level of the influx of Ca(2+) across neuronal membranes that triggers cellular damage, and the fraction of oligomeric species bound to the membrane. Our findings indicate that the susceptibility of neuronal cells to different types of misfolded oligomeric assemblies is directly related to the extent of binding of such oligomers to the cellular membrane.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio" and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Elisa
E
Evangelisti
Department of Experimental and Clinical Biomedical Sciences "Mario Serio" and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Roberta
R
Cascella
Department of Experimental and Clinical Biomedical Sciences "Mario Serio" and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Matteo
M
Becatti
Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3, 50019 Florence, Italy.
Giovanna
G
Marrazza
Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK.
Christopher M
CM
Dobson
Department of Experimental and Clinical Biomedical Sciences "Mario Serio" and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Fabrizio
F
Chiti
Department of Experimental and Clinical Biomedical Sciences "Mario Serio" and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Massimo
M
Stefani
Department of Experimental and Clinical Biomedical Sciences "Mario Serio" and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Cristina
C
Cecchi
D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D019878:Carboxyl and Carbamoyl Transferases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D055503:Protein Multimerization; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D020349:Surface Plasmon Resonance
D000682:Amyloid; D016229:Amyloid beta-Peptides; D029968:Escherichia coli Proteins; D017470:Receptors, Glutamate; D005677:G(M1) Ganglioside; D002784:Cholesterol; D019878:Carboxyl and Carbamoyl Transferases; C504838:hypF protein, E coli; D002118:Calcium