Prion transmission prevented by modifying the β2-α2 loop structure of host PrPC

Area of Science:

• Prion biology
• Molecular biology
• Neuroscience

Background:

• Zoonotic prion transmission, such as variant Creutzfeldt-Jakob disease (vCJD) linked to bovine spongiform encephalopathy (BSE), poses significant public health risks.
• Cross-species prion transmission is difficult to predict and assess.
• The β2-α2 loop of the prion protein (PrP) is a key determinant in interspecies prion conversion.

Purpose of the Study:

• To investigate the role of specific amino acid substitutions in the β2-α2 loop of mouse PrP in modulating cross-species prion transmission.
• To determine the impact of the Y169G substitution, along with S170N and N174T, on prion infectivity in vivo and in vitro.

Main Methods:

• Utilized transgenic mice expressing modified mouse PrP with a triple-amino acid substitution (Y169G, S170N, N174T) in the β2-α2 loop.
• Assessed prion resistance in these mice following inoculation with various prion strains, including mouse prions and deer chronic wasting disease (CWD) prions.
• Conducted in vitro prion conversion assays to evaluate the biochemical impact of the substitutions.

Main Results:

• Transgenic mice expressing mouse PrP with the Y169G, S170N, and N174T substitutions demonstrated complete resistance to infection by two strains of mouse prions.
• These mice were also resistant to infection by deer CWD prions.
• The Y169 residue, crucial for maintaining loop structure, was found to be important for prion formation.

Conclusions:

• The Y169G substitution, in conjunction with S170N and N174T, confers robust resistance to prion infection in mice.
• Structural variations in the β2-α2 loop of the prion protein can effectively modulate interspecies prion transmission.
• These findings offer insights into strategies for preventing prion disease transmission across species.