title: Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-Sträussler-Scheinker disease amyloid protein.
abstract: 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.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milano, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Fioriti
authors.forename: Nadia
authors.initials: N
authors.lastname: Angeretti
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Ada
authors.initials: A
authors.lastname: De Luigi
authors.forename: Alessio
authors.initials: A
authors.lastname: Colombo
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D016098:Gerstmann-Straussler-Scheinker Disease / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D018620:PrPSc Proteins / Q000235:genetics / Q000633:toxicity* / Q000648:ultrastructure; D051381:Rats; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D018620:PrPSc Proteins; D014316:Tritium; D010751:Phosphopyruvate Hydratase; D013936:Thymidine