NMR spectroscopy has revealed significant difference between the infectious and non-infectious form of prions, errant proteins that replicate by converting other proteins into copies of themselves. The finding could lead to new insights into how prions cause brain diseases, such as CJD and may one day lead to a way to stop their spread.

Infectious proteins known as prions have been identified as the underlying biochemical cause of so-called "mad cow" disease (bovine spongiform encephalopathy BSE), the ovine equivalent, scrapie, and, of course the devastating human illness Creuzfeldt-Jakob disease (CJD), kuru, and a hereditary form of dementia known as Gertsmann-Straeussler-Scheinker disease. The causative agents are incorrectly folded proteins that somehow infect other healthy proteins in the brain, causing those to misfold too, although the details are not entirely clear.

The word prion derives from the term Proteinaceous Infectious particle, similar to a virus, but lacking any genetic material. Stanley Prusiner received the 1997 Nobel Prize in Physiology or Medicine for his discovery of prions. Pathogenic prions are dangerous because they can convert physiological, non-pathogenic molecules into the diseased form. A metaphor for this process lies in the "self-replication" of Agent Smith from the well-known Matrix series of science fiction movies.

A team headed by Beat Meier of the Eidgenössische Technische Hochschule (ETH Zurich) in Switzerland and Raimon Sabaté of the University of Bordeaux, France hoped to answer the question: Why are some proteins infectious while others are not? They have now used NMR spectroscopy to examine the protein domains of two different forms, polymorphs, of a prion-forming protein. Writing in the journal Angewandte Chemie, the researchers report that the molecular structures of the infectious and non-infectious forms are very different.

Prions usually consist of β-sheet structures. These are accordion-like folded protein ribbons that can easily aggregate into thread-like structures, known as amyloid fibrils, which are present in the brains of CJD and Alzheimer's sufferers.

Beat, Sabaté, and their colleagues investigated the prion-forming domain of the fungal protein HET-s. At neutral pH (pH 7) and under physiological conditions, this domain forms infectious fibrils. However, it also forms fibrils in acidic solution, at pH 3, but these are not infectious.

The team turned to NMR spectroscopy to take a close look at this protein and so obtain information about the protein's chemical environment, its structure and its molecular dynamics. Such aspects of protein chemistry are not necessarily available to techniques such as X-ray crystallography, but are now increasingly amenable to powerful NMR techniques.

NMR revealed two very different spectra at pH 7 and pH 3 for the two versions of the prion. Both follow the rigid β-sheet structure in broad terms. However, when viewed much close up the structures diverge widely. Particularly striking is the fact that the infectious pH 7 form has highly flexible loops in addition to the rigid domains. These are absent from the non-infectious pH 3 prions, the researchers explain.

"The lack of infectiousness of the pH 3 fibrils is thus related to the fact that their molecular structure is significantly different from that of the fibrils formed at physiological pH," the researchers conclude. Indeed, the researchers add that, their results suggest that low-pH fibrils are not infectious because their structure differs substantially from that accessible at physiological pH. This finding will translate into new insights into how prion diseases may progress and in the much longer term will help inform research into possible new treatments.

Related links:

• Angew Chem Int Edn, 2008, in press
• Meier page

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.