The role of prion protein sequence in cross‐species prion transmission (153.2)

Abstract

Prion diseases are fatal neurodegenerative diseases caused by the conversion of normal cellular prion protein, PrPC, to a misfolded isoform known as PrPSc. Zoonotic prion transmission was reported during the bovine spongiform encephalopathy (BSE) epidemic, yet assessing the risk of cross‐species prion transmission remains challenging. We and others have studied how specific amino acid residue differences between species impact prion conversion, and have found the β2‐α2 loop region of the prion protein (residues 165‐175) markedly influences transmission. Here we examined the impact of amino acid substitutions within the loop on cross‐species prion transmission in vivo and in vitro. We found that transgenic mice expressing β2‐α2 loop substitutions completely resisted infection with two strains of mouse prions and with deer CWD prions. To investigate the impact of individual amino acid residues on conversion, we used an in vitro conversion assay and found that substitutions at certain residues within the loop, such as position 169, dramatically reduced conversion whereas other substitutions had no effect. We propose a model based on steric zipper interactions to explain these results. These studies indicate that the β2‐α2 loop modulates cross‐species prion transmission and suggest this region as a target for rational therapeutic design.Grant Funding Source: NS055116, NS069566, and U54AI0359