Characterising structural variations of prion proteins
Funded by BBSRC-CSG
Associated scientists: Miss Sonya Agarwal and Dr Andrew C. Gill
In most species studied to date, the prion protein has been identified in several allelic variants. This includes man, where the residue encoded at codon 129 can be either methionine or valine, mice, where polymorphisms exist at codons 108 and 189 and sheep, which has the most heterogeneous PrnP gene of any mammal studied. It is clear that these polymorphisms affect TSE disease characteristics, such as incubation times and susceptibilities. In extreme cases, polymorphisms in the Prnp gene can result in spontaneous disease. The molecular mechanisms by which these effects are modulated are less clear but presumably involve alterations in prion protein structure, stability and/or molecular interactions and PrPC function. This project aims to use various techniques to probe differences in prion protein properties that may impinge on the ability of these proteins to convert to pathogenic isoforms. This includes in vitro misfolding assays, molecular dynamics studies and studies of protein stability. We also aim to characterise those sites not typically associated with susceptibility, since they are not naturally polymorphic. We are currently developing methods to investigate the identities of the various possible misfolded isoforms of PrP that can be created in vitro to assess their relevance to in vivo disease.