US scientists report that prions, infamously linked to mad cow disease, have crucial subsections that control their behaviour, including whether or not they can cross between species.

Disease prions, which cause neurodegenerative diseases like Cruetzfeld-Jakob disease (CJD), are misfolded proteins that trigger the misfolding of neighbouring healthy prions. The prions causing CJD in humans, and bovine spongiform encephalopathy (BSE) in cows, generate damaging clumps of misfolded proteins, called amyloids, in the brain.

Susan Lindqvist and Peter Tessier at the Whitehead Institute for Biomedical Research have now shown that prion behaviour is dictated by short subsections of the protein. These regions, typically 10 per cent of the molecule, not only define how the protein folds, but also act as the template that triggers neighbouring proteins to re-fold, forming amyloids. Further, these elements decide whether or not the prion can cross from one species to another.

Lindquist and Tessier discovered these short 'recognition elements' while studying prions in yeasts. The team used arrays of proteins bound to a surface, monitoring protein folding in real time. Future work using the arrays will include studying how prions that cause both BSE and CJD manage to cross the species barrier, said Tessier.

It was surprising to find that short prion subsections control how the whole protein folds, said Tessier. Protein folding typically involves large numbers of interactions across the molecule. The discovery raises the possibility that subsections controlling whole peptide folding could be a more widespread phenomenon. 'You can't know until you look,' said Tessier. 'But we're in the process of searching among prion and non-prion amyloid-forming proteins,' he said.

David Brown, who researches prion disease at the University of Bath, UK, cautioned that the relationship between yeast and mammalian prions shouldn't be over interpreted. However, 'the microarray technique could be applied to other systems, such as mammalian prion proteins,' he said.

Not all prions are associated with disease, said Lindquist - some may have beneficial effects, such as adaptation to cope with environmental stress.

James Mitchell Crow

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