NR AXSD
AU Manzoni,C.; Colombo,L.; Gobbi,M.; Beeg,M.; Natalello,A.; Doglia,S.M.; Morbin,M.; Tagliavini,F.; Forloni,G.; Salmona,M.
TI Role of Oligomers in the Neurotoxicity of Gerstmann-Sträusler-Scheinker Disease Amyloid Protein
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.64
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB In prion diseases, PrP-amyloid is found in the brain of patients suffering from Gerstamann-Sträussler-Scheinker disease (GSS), PrP cerebral amyloid angiopathy, variant CJD and kuru. In familial GSS the amyloid plaques are mainly composed of a prion protein fragment encompassing residues 81/82-145/146. We previously showed that a synthetic peptide spanning residues 82-146 readily forms fibrils and has the physicochemical features accounting for the massive amyloid deposition of PrP in GSS. Moreover, PrP82-146 was found to be toxic to cortical neurons. Therefore we have focussed our attention on the first stages of PrP82-146 fibrillization. In particular, by using a photo-induced-cross-linking technique, we have demonstrated that this peptide forms oligomeric species constituted mostly by dimers and trimers and, at a lower extent, by larger structures up to 15-mers. Electron microscopy analysis revealed that PrP82-146 aggregation is a step-wise process starting with formation of oliogomers and protofilaments, which combine to produce the amyloid fibrils. FT/IR analysis showed that monomers are mainly unstructured and form low order aggregates after 7 days. At this stage, the FT-IR bands at 1623.2 cm-1 and at 1689.8 cm-1 suggested that the early aggregates were characterized by an antiparallel ßsheet intermolecular interaction. After 10 days, the presence of the band at 1626.1 cm1 suggested assembly into mature fibrils. Cellular toxicity of PrP82-146 paralleled the fibrilllization process since the biological effects were evident only after the commencement of the structural rearrangement. In particular, the presence of oligomers was a committed step for the toxic effect since the addition of an antioligomer antibody abolished all biological effects. Stable soluble oligomers were also toxic to cells and noteworthy with an inverse correlation with their size. In conclusion, in GSS prefibrillar oligomers may play a role in the neurodegenerative process
AD C. Manzoni, L. Colombo, M. Gobbi, M. Beeg, M. Salmona, Istituto di Ricerche Farmacologiche, Department Molecular Biochemistry and Pharmacology, Italy; A. Natalello, S.M. Doglia, Università Milano-Bicocca, Department of Biotechnology and Bioscience, Italy; M. Morbin, F. Tagliavini, Fondazione IRCCS Istituto Neurologico, Italy; G. Forloni, Istituto di Ricerche Farmacologiche, Department of Neuroscience, Italy
SP englisch
PO Schottland