NR AVWI
AU Fioriti,L.; Angeretti,N.; Colombo,L.; De Luigi,A.; Colombo,A.; Manzoni,C.; Morbin,M.; Tagliavini,F.; Salmona,M.; Chiesa,R.; Forloni,G.
TI Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-Sträussler-Scheinker disease amyloid protein
QU Journal of Neuroscience 2007 Feb 14; 27(7): 1576-83
PT journal article; research support, non-u.s. gov't
AB Amyloid fibrils in Gerstmann-Sträussler-Scheinker (GSS) disease are composed of a fragment of the prion protein (PrP), the N and C termini of which correspond to ragged residues 81-90 and 144-153. A synthetic peptide spanning the sequence 82-146 (PrP 82-146) polymerizes into protease-resistant fibrils with the tinctorial properties of amyloid. We investigated the biological activity of PrP 82-146 and of two nonamyloidogenic variants of PrP 82-146 with scrambled amino acid sequence 106-126 or 127-146. Cortical neurons prepared from rat and mouse embryos were chronically exposed to the PrP 82-146 peptides (10-50 microM). PrP 82-146 and the partially scrambled peptides induced neuronal death with a similar dose-response pattern, indicating that neurotoxicity was independent of amyloid fibril formation. Neurotoxicity was significantly reduced by coadministration of an anti-oligomer antibody, suggesting that PrP 82-146 oligomers are primarily responsible for triggering cell death. Neurons from PrP knock-out (Prnp0/0) mice were significantly less sensitive to PrP 82-146 toxicity than neurons expressing PrP. The gliotrophic effect of PrP 82-146 was determined by [methyl-3H]-thymidine incorporation in cultured astrocytes. Treatment with PrP 82-146 stimulated [methyl-3H]-thymidine uptake 3.5-fold. This activity was significantly less when the 106-126 or 127-146 regions were disrupted, indicating that PrP 82-146 amyloid activates the gliotrophic response. Prnp0/0 astrocytes were insensitive to the proliferative stimulus of PrP 82-146. These results underline the role of cerebral accumulation of abnormally folded PrP fragments and indicate that cellular PrP governs the pathogenic process.
MH Amino Acid Sequence; Amyloid/*chemistry/ultrastructure; Analysis of Variance; Animals; Animals, Newborn; Apoptosis/drug effects; Astrocytes/*drug effects; Cell Survival/drug effects; Cells, Cultured; Cerebral Cortex/cytology; Embryo; Gerstmann-Sträussler-Scheinker Disease/*metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Neuroblastoma; Neurons/*drug effects; Peptide Fragments/chemistry/genetics/toxicity/ultrastructure; Phosphopyruvate Hydratase/metabolism; PrPsc Proteins/genetics/*toxicity/ultrastructure; Rats; Thymidine/metabolism; Time Factors; Tritium/metabolism
AD Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milano, Italy.
SP englisch
PO USA