Structural characterization of beta-sheeted oligomers formed on the pathway of oxidative prion protein aggregation in vitro.
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Structural characterization of beta-sheeted oligomers formed on the pathway of oxidative prion protein aggregation in vitro. / Redecke, Lars; von Bergen, Martin; Clos, Joachim; Konarev, Peter V; Svergun, Dimitri I; Fittschen, Ursula E A; Broekaert, José A C; Bruns, Oliver; Georgieva, Dessislava; Mandelkow, Eckhard; Genov, Nicolay; Betzel, Christian.
In: J STRUCT BIOL, Vol. 157, No. 2, 2, 2007, p. 308-320.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Structural characterization of beta-sheeted oligomers formed on the pathway of oxidative prion protein aggregation in vitro.
AU - Redecke, Lars
AU - von Bergen, Martin
AU - Clos, Joachim
AU - Konarev, Peter V
AU - Svergun, Dimitri I
AU - Fittschen, Ursula E A
AU - Broekaert, José A C
AU - Bruns, Oliver
AU - Georgieva, Dessislava
AU - Mandelkow, Eckhard
AU - Genov, Nicolay
AU - Betzel, Christian
PY - 2007
Y1 - 2007
N2 - The pathology of transmissible spongiform encephalopathies (TSEs) is strongly associated with the structural conversion of the cellular prion protein (PrPC) into a misfolded isoform (PrPSc) that assembles into amyloid fibrils. Since increased levels of oxidative stress have been linked to prion diseases, we investigated the metal-induced oxidation of human PrP (90-231). A novel in vitro conversion assay based on aerobic incubation of PrP in the presence of elemental copper pellets at pH 5 was established, resulting in aggregation of highly beta-sheeted prion proteins. We show for the first time that two discrete oligomeric species of elongated shape, approx. 25 mers and 100 mers, are formed on the pathway of oxidative PrP aggregation in vitro, which are well characterized regarding shape and size using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and electron microscopy (EM). Considering that small oligomers of highly similar size have recently been reported to show the highest specific infectivity within TSE-infected brain tissues of hamsters, the novel oligomers observed in this study are interesting candidates as agent causing neurodegenerative and/or self-propagating effects. Moreover, our results significantly strengthen the theory that oxidative stress might be an influence that leads to substantial structural conversions of PrP in vivo.
AB - The pathology of transmissible spongiform encephalopathies (TSEs) is strongly associated with the structural conversion of the cellular prion protein (PrPC) into a misfolded isoform (PrPSc) that assembles into amyloid fibrils. Since increased levels of oxidative stress have been linked to prion diseases, we investigated the metal-induced oxidation of human PrP (90-231). A novel in vitro conversion assay based on aerobic incubation of PrP in the presence of elemental copper pellets at pH 5 was established, resulting in aggregation of highly beta-sheeted prion proteins. We show for the first time that two discrete oligomeric species of elongated shape, approx. 25 mers and 100 mers, are formed on the pathway of oxidative PrP aggregation in vitro, which are well characterized regarding shape and size using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and electron microscopy (EM). Considering that small oligomers of highly similar size have recently been reported to show the highest specific infectivity within TSE-infected brain tissues of hamsters, the novel oligomers observed in this study are interesting candidates as agent causing neurodegenerative and/or self-propagating effects. Moreover, our results significantly strengthen the theory that oxidative stress might be an influence that leads to substantial structural conversions of PrP in vivo.
M3 - SCORING: Zeitschriftenaufsatz
VL - 157
SP - 308
EP - 320
JO - J STRUCT BIOL
JF - J STRUCT BIOL
SN - 1047-8477
IS - 2
M1 - 2
ER -
