Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases.
Amyloid fibrillization is multistep process involving soluble oligomeric intermediates, including spherical oligomers and protofibrils. Amyloid oligomers have a common, generic structure, and they are intrinsically toxic to cells, even when formed from non-disease related proteins, which implies they also share a common mechanism of pathogenesis and toxicity. Here we report that soluble oligomers from several types of amyloids specifically increase lipid bilayer conductance regardless of the sequence, while fibrils and soluble low molecular weight species have no effect. The increase in membrane conductance occurs without any evidence of discrete channel or pore formation or ion selectivity. The conductance is dependent on the concentration of oligomers and can be reversed by anti-oligomer antibody. These results indicate that soluble oligomers from many types of amyloidogenic proteins and peptides increase membrane conductance in a conformation-specific fashion and suggest that this may represent the common primary mechanism of pathogenesis in amyloid-related degenerative diseases.
Kayed
Rakez
R
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
Sokolov
Yuri
Y
Edmonds
Brian
B
McIntire
Theresa M
TM
Milton
Saskia C
SC
Hall
James E
JE
Glabe
Charles G
CG
D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D052160:Benzothiazoles; D002462:Cell Membrane / Q000378:metabolism; D002845:Chromatography; D004594:Electrophysiology; D006801:Humans; D007477:Ions; D008051:Lipid Bilayers / Q000737:chemistry*; D008854:Microscopy, Electron; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors; D014162:Transfection
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D007477:Ions; D008051:Lipid Bilayers; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T