Interaction of the 106-126 prion peptide with lipid membranes and potential implication for neurotoxicity.
Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and beta-sheet rich pathogenic isoform (PrP(SC)) of the cellular prion protein (PrP(C)). In the present work, we were interested to study the mode of prion protein interaction with the membrane using the 106-126 peptide and small unilamellar lipid vesicles as model. As previously demonstrated, we showed by MTS assay that PrP 106-126 induces alterations in the human neuroblastoma SH-SY5Y cell line. We demonstrated for the first time by lipid-mixing assay and by the liposome vesicle leakage test that PrP 106-126, a non-tilted peptide, induces liposome fusion thus a potential cell membrane destabilization, as supported by membrane integrity assay (LDH). By circular dichroism (CD) analysis we showed that the fusogenic property of PrP 106-126 in the presence of liposome is associated with a predominantly beta-sheet structure. These data suggest that the fusogenic property associated with a predominant beta-sheet structure exhibited by the prion peptides contributes to the neurotoxicity of these peptides by destabilizing cellular membranes. The latter might be attached at the membrane surface in a parallel orientation as shown by molecular modeling.
Dupiereux
Ingrid
I
Department of Human Histology, CRPP, University of Liège, Institute of Pharmacy-CHU 1, avenue de l'Hôpital, Sart Tilman, 4000 Liège, Belgium.
Zorzi
Willy
W
Lins
Laurence
L
Brasseur
Robert
R
Colson
Pierre
P
Heinen
Ernst
E
Elmoualij
Benaïssa
B
D045744:Cell Line, Tumor; D002942:Circular Dichroism; D006801:Humans; D050356:Lipid Metabolism; D008561:Membrane Fusion; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013056:Spectrophotometry, Ultraviolet
D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126)