1887

Abstract

Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP) to a misfolded, pathogenic isoform (PrP). Prion inoculation experiments in mice expressing homologous PrP molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP, our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein () or interleukin-1 receptor, type I (), and transgenic overexpression of human superoxide dismutase 1 () prolonged incubation times by 13, 16 and 19 %, respectively.

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2019-11-19
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