Research

Prion protein polymerisation triggered by manganese-generated prion protein seeds


Reference:

Hesketh, S., Thompsett, A. R. and Brown, D. R., 2012. Prion protein polymerisation triggered by manganese-generated prion protein seeds. Journal of Neurochemistry, 120 (1), pp. 177-189.

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Official URL:

http://dx.doi.org/10.1111/j.1471-4159.2011.07540.x

Abstract

Prion diseases are neurodegenerative diseases that can be transmitted between individuals. The exact cause of these diseases remains unknown. However, one of the key events associates with the disease is the aggregation of a cellular protein, the prion protein. The mechanism of this is still unclear. However, it is likely that the aggregation is trigged by a seeding mechanism in which an oligomer of the prion protein is able to catalyse polymerisation of further prion protein into larger aggregates. We have developed a model of this process using an oligomeric species generated from recombinant protein by exposure to manganese. On fractionation of the seeding species, we estimated that the smallest size the oligomer would be is an octomer. We analysed the catalytic mechanism of the seeding oligomer and its interaction with substrate. Different domains of the protein are necessary for the seeding ability of the prion protein as opposed to those required for it to form a substrate for the polymerisation reaction. Prion seeds formed from different sheep alleles are able to reproduce the characteristics of scrapie in terms of resistance to disease. However, we were also able to generate prion seed from chicken PrP a species where no prion disease is known. Our findings provide an insight into the aggregation process of the prion protein and its potential relation to disease progress.

Details

Item Type Articles
CreatorsHesketh, S., Thompsett, A. R. and Brown, D. R.
DOI10.1111/j.1471-4159.2011.07540.x
Uncontrolled Keywordsaggregation, prion, manganese, cjd, bovine spongiform encephalopathy, scrapie
DepartmentsFaculty of Science > Biology & Biochemistry
RefereedYes
StatusPublished
ID Code28292

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