PubMed1997
Prion-related encephalopathies are characterized by astrogliosis and nerve cell degeneration and loss. These lesions might be the consequence of an interaction between the abnormal isoform of the cellular prion protein that accumulates in nervous tissue and the plasma membranes. Previously we found that a synthetic peptide, homologous to residues 106-126 of the human prion protein, is fibrillogenic and toxic to neurons and trophic to astrocytes in vitro. This study dealt with the ability of the peptide to interact with membranes. Accordingly, we compared PrP 106-126 with different synthetic PrP peptides (PrP 89-106, PrP 127-147, a peptide with a scrambled sequences of 106-126, and PrP 106-126 amidated at the C-terminus) as to the ability to increase the microviscosity of artificial and natural membranes. The first three had no effect on nerve and glial cells in vitro, whereas the amidated peptide caused neuronal death. Using a fluorescent probe that becomes incorporated into the hydrocarbon core of the lipid bilayer and records the lipid fluidity, we found PrP 106-126 able to increase significantly the membrane microviscosity of liposomes and of all cell lines investigated. This phenomenon was associated with the distribution of the peptide over the cell surface, but not with changes in the membrane lipid or protein content, or with membrane lipid phase transitions. Accordingly, we deduced that increased membrane microviscosity was unrelated to changes in the membrane native components and was the result of increased lipid density following PrP 106-126 embedding into the lipid bilayer. No control peptides had comparable effects on the membrane microviscosity, except PrP 106-126 amidated at the C-terminus. Since the latter was as neurotoxic, but not as fibrillogenic, as PrP 106-126, we argued that the ability of PrP 106-126 to increase membrane microviscosity was unrelated to the propensity of the peptide to raise fibrils. Rather, it could be connected with the primary structure of PrP 106-126, characterized by two opposing regions, one hydrophilic and the other hydrophobic, that enabled the peptide to interact with the lipid bilayer. Based on these findings, we speculated that the glial and nerve cell involvement occurring in prion-related encephalopathies might be caused by the interaction with the plasma membrane of a PrP 106-126-like fragment or of the sequence spanning residues 106-126 of the abnormal isoform of the prion protein.