Tiny differences between mammalian and non-mammalian prion proteins could be responsible for transmissible spongiform encephalopathies (TSEs) such as Creutzfeld-Jacob disease, say Italian scientists. TSEs are generally accepted to be caused by prions in the brain folding into an abnormal form; this triggers other prions to refold, creating plaques and tangles.

Models imply greater force is needed to stretch mammalian prions

Carmelo La Rosa at the University of Catania and colleagues used molecular dynamics simulations to probe the difference between prion proteins in two mammals, humans and Syrian hamsters, and two non-mammals, chickens and turtles. TSEs have not been reported in chickens or turtles.

The group used the simulations to model the prions, to see how far they could stretch and still refold into their native state. The team found that a greater force was needed to unfold the mammalian prions. However, once unfolded, these prions refolded into the native state less efficiently than the turtle or chicken proteins, adopting metastable configurations instead.

La Rosa hopes that mechanistic research such as this will lead to treatments for TSEs. At present, there are no cures for prion diseases in humans or livestock, he said. 'The detailed characterisation of the metastable states in the early steps of prion misfolding is a highly promising prerequisite for anti-prion molecule design.' But, he warned that further work needs to be done towards making the simulations more realistic. 'In particular, we will repeat the simulations with prions linked to cell membranes,' he said. The group also intends to design simulations to work out whether other factors such as temperature or pH have the same effect on prion unfolding as mechanical stretching.

Colin Batchelor