Prions and Diseases by Wen-Quan Zou & Pierluigi Gambetti

Author:Wen-Quan Zou & Pierluigi Gambetti
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

9.3.3 Effect of Prnp Heterozygosity

Heterozygosity at the Prnp gene may also influence TSE species barriers. In vivo, transgenic mice expressing both mouse and hamster PrPC are susceptible to infection with mouse and hamster scrapie, but mouse scrapie incubation times are significantly increased when hamster PrPC is present (Scott et al. 1989). In vitro, expression of hamster PrPC in mouse scrapie-infected cells can completely abolish PrPSc formation (Priola et al. 1994). This phenomenon, known either as interference (Priola et al. 1994) or dominant negative inhibition (Zulianello et al. 2000), is seen when heterologous PrPC and PrPSc molecules bind but PrPC is not subsequently converted to PrPSc. Interference may explain why all clinical cases of vCJD in humans are homozygous for methionine at codon 129 and why heterozygosity at codon 129 might be protective. A valine at codon 129 would block vCJD PrPSc formation from the susceptible PrPC methionine 129 molecules in a dominant-negative fashion, slowing down or preventing clinical disease. In this manner, heterozygosity at the Prnp allele may contribute to the maintenance of TSE species barriers.

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