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Journal of the American Osteopathic Association


Hypothesis: Prion species barrier may be due to genetic variation and protein structural differences among different species.

Methods: Sequence analyses of open reading frames of the prion gene from different species, including human, deer, sheep, cattle, mouse, and rat were conducted. Synthetic prion-derived peptides with strategic point mutations were manufactured and studied to investigate potential conformational changes.

Results: Codon 129 is a polymorphism position where, in the human population, 50% is Met (Methionine)/Val (Valine), 40% Met/Met, 10% Val/Val. Other species: sheep, cattle, rat, and mouse have a conserved codon 129 with Met/Met. It is observed that with Met at codon 129, transmission of prion disorder is relatively consistent regarding incubation time. However, if codon 129 is other than Met, eg, Valine in rat, Leucine (Leu) in Wapiti deer, incubation time of prion disorder is inconsistent or prolonged. Furthermore, there are four putative alpha-helical regions forming four-helix bundles in the prion protein which are proposed to be critical in the stability of the protein. If these alpha-helical regions convert to beta-pleated sheets, the altered prion protein accumulates in the brain tissues and degenerative changes occur. Prion-derived peptide 121-231, containing Met at codon 129, demonstrated alpha-helical conformation under nuclear magnetic resonance (NMR). However, if Val or Leu is at codon 129, prion-derived peptide 121-231 demonstrated beta-pleated sheet conformation under NMR analysis.

Conclusions: Prion species barrier may be, at least in part, explained by differences in genetic and/or protein structural variations among different species.



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Prions, Codon, Genetics