NR AURR
AU Redecke,L.; Silvestric,M.; von Bergen,M.; Svergun,D.I.; Konarev,P.V.; Georgieva,D.; Genov,N.; Betzel,C.
TI Structurally Distinct ß-Sheeted Oligomers are formed on the Pathway of Oxidative Prion Protein Aggregation in vitro
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Poster: Struktur und molekulare Mechanismen MOL-15
PT Konferenz-Poster
AB
The pathology of prion diseases is strongly associated with the posttranslational conversion of the cellular prion protein (PrPc) into a misfolded infectious state (PrPsc) that assembles into amyloid fibrils. In addition to several other mechanisms, oxidative stress has been proposed to be a pivotal event in the course of the disease, similarly to its role in other neurodegenerative disorders. However, the detailed molecular mechanisms of neuronal cell death and of prion infectivity remain still enigmatic. While these effects have been assigned to the amyloid aggregates in the past, recent investigations strongly supported the highly infective nature of low oligomeric states of the misfolded PrP. Consequently, the detailed investigation of the intermediates formed on the pathway of PrP aggregation is of fundamental importance in light of the ongoing search for the infectious and neurotoxic species of PrPsc.
In this context, we comparatively investigated the structural changes of recombinant human PrP (90-231) and mouse PrP (89-230) induced by a novel in vitro conversion assay. Aerobic incubation of PrP in the presence of elemental copper pellets at pH 5 established a redox-system in solution that results in oxidative damage of PrP, which is directly accompanied by structural conversion and aggregation of highly ß-sheeted PrP-isoforms. Compared to mouse PrP, the conversion and aggregation of human PrP was slightly accelerated. Using small-angle X-ray scattering (SAXS) techniques, we show for the first time that two well-defined soluble oligomers of distinct shape are formed on the pathway of oxidative PrP aggregation, which were shown to be indistinguishable between human and mouse PrP. The characteristic hydrodynamic radii have been determined to be approx. 10 and 18 nm. Consequently, these novel oligomers are interesting candidates as agent causing neurodegenerative and/or self-propagating effects.
AD Lars Redecke, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, University Hospital Hamburg-Eppendorf, c/o DESY, 22603 Hamburg, Germany; Marko Silvestric, Dessislava Georgieva, Christian Betzel, Institute of Biochemistry and Food Chemistry, University of Hamburg, 20146 Hamburg, Germany; Martin von Bergen, Max-Planck-Unit for Structural Molecular Biology, Notkestr. 85, 22607 Hamburg, Germany; Dimitri I. Svergun, Peter V. Konarev, European Molecular Biology Laboratory (EMBL), Outstation Hamburg at DESY, 22603 Hamburg, Germany; Nicolay Genov, nstitute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria.
SP englisch
PO Deutschland
OR Tagungsband