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Generation of hydrogen peroxide from mutant forms of the prion protein fragment PrP121-231.

Turnbull, Stuart and Tabner, Brian J. and Brown, David R. and Allsop, David (2003) Generation of hydrogen peroxide from mutant forms of the prion protein fragment PrP121-231. Biochemistry, 42 (25). pp. 7675-7681. ISSN 0006-2960

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Abstract

By means of electron spin resonance spectroscopy, in conjunction with the spin trapping technique, we have shown previously that A and -synuclein (aggregating proteins that accumulate in the brain in Alzheimer's disease, Parkinson's disease, and related disorders) both induce the formation of hydroxyl radicals following incubation in solution, upon addition of Fe(II). These hydroxyl radicals are apparently formed from hydrogen peroxide, via Fenton's reaction. An N-terminally truncated fragment of the mouse prion protein (termed PrP121-231) is toxic to cerebellar cells in culture, and certain human mutations, responsible for inherited prion disease, enhance this toxicity. Here we report that PrP121-231 containing three such mutations (E200K, D178N, and F198S) also generated hydroxyl radicals, upon addition of Fe(II). The formation of these radicals was blocked by catalase, or by metal chelators, each of which also reduced the toxicity of the PrP121-231 fragments to cultured normal mouse cerebellar cells. Wild-type PrP121-231, full-length cellular PrP, and its homologue doppel did not generate any detectable hydroxyl radicals. We conclude that the additional cytotoxic effects of the mutant forms of PrP121-231 could be due to their ability to generate hydrogen peroxide, by a metal-dependent mechanism. Thus, one effect of these (and possibly other) prion mutations could be production of a particularly toxic form of the prion protein, with an enhanced capacity to induce oxidative damage, neurodegeneration, and cell loss.

Item Type: Article
Journal or Publication Title: Biochemistry
Subjects: Q Science > QH Natural history > QH301 Biology
Departments: Faculty of Science and Technology > Lancaster Environment Centre
Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 8853
Deposited By: Prof David Allsop
Deposited On: 15 May 2008 11:44
Refereed?: Yes
Published?: Published
Last Modified: 09 Apr 2014 22:14
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/8853

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