A team composed of researchers from across the globe and including scientists from ETH Zurich and the University of Zurich has created a new disease, comparable to BSE, in laboratory mice. The team showed that exchanging just two amino acids in the structure of the prion protein is enough to trigger a disease.
The starting point of the project was the discovery by the team led by ETH Zurich Nobel prize-winner Kurt Wüthrich of a structural peculiarity in the prion protein of moose and deer.
Kurt Wüthrich says that it all began with the resolving of the structure of the prion protein in mammals: "A small region of this protein, the region between the 166th and 175th amino acids, forms a loop close to the surface of the protein." The ETH Zurich Professor of Biophysics was awarded the Nobel Prize for Chemistry in 2002 for his fundamental discoveries in the field of protein structural analysis. "Our analyses using nuclear magnetic resonance spectroscopy (NMR) showed that this loop has an irregular shape in the prion proteins of humans, cattle, sheep and other mammals, but, astonishingly, it is precisely defined in moose and deer."
Prion disease in deer and moose not under control
The fact that up to 20 percent of all the deer and moose living wild in the USA and Canada suffer from Chronic Wasting Disease (CWD), an infectious prion disease comparable to mad cow disease (BSE), is not well known in Europe. In this disease, as in BSE and in Creutzfeldt-Jakob Disease in humans, misfolded versions of one of the body’s own proteins lead to deposits and finally to the death of nerve cells. It is assumed that heredity also plays a part in the transmission of the disease. The shape of the prion protein characteristic of moose could now give new impetus to efforts to explain CWD and other prion diseases.
Up to 100 percent of the mice with the new gene become ill
Using the conspicuous moose prion protein for further studies of prion diseases seemed the obvious thing to do. First of all, Kurt Wüthrich’s team showed that the type of amino acids at positions 170 and 174 has a decisive influence on whether the suspect loop in the prion protein adopts a rigid or a flexible shape. The researchers now took advantage of this to test the possible effects of the rigid loop in animal experiments.
The results of this study were published in the scientific journal PNAS on 6 January 2009.
In Adriano Aguzzi’s laboratory at the University Hospital Zurich, Christina Sigurdson created a prion gene in mice with two so-called point mutations which, in the living animal, manufactures the mutant form of the mouse prion protein being studied by Wüthrich’s team and containing the rigid loop of the moose prion protein instead of a flexible loop. The researchers were astonished by the fact that, over time, all the transgenic mice carrying this artificial prion protein developed a new, transmissible and fatal prion disease. The deposits which are typical of this disease and which successively damage the organ and finally destroy it accumulated in their brains, with the mice displaying the corresponding symptoms of neurological defects.
Insights still unimaginable at the start of the research
Christina Sigurdson told Science Daily that, "We also discovered that the transfer of brain tissue from mice with the altered protein into normal mice also triggers the prion disease." She says that the fact that an infectious disease can be generated by two mutations in the prion gene deliberately introduced into the mouse prion protein is of particular scientific interest. According to Sigurdson, "This new mouse model of the disease may help us to understand how the incorrectly folded protein causes nerve cell degeneration – and it helps in the search for effective treatments for prion diseases."
Kurt Wüthrich adds, "For us, it’s a marvellous story." He says it emphasizes once again the outstanding importance of basic research undertaken without any motive for short-term profit.
According to Wüthrich, "We determined the NMR structure of a prion protein, that of the mouse, for the first time twelve years ago. We introduced the NMR method to resolve protein structures 25 years ago, with the Swiss physicist Felix Bloch and the American Edward Purcell having carried out the first NMR experiments more than 60 years ago. At none of these milestones could the researchers have dreamt that subtle NMR observations on a protein molecule would lead us directly to a new form of a hitherto incompletely characterised, infectious and fatal disease."
BSE: Sounding the all clear would be out of place
Using meat and bone meal as animal feed played a central role in the BSE crisis in Switzerland. A ban on feeding meat and bone meal to ruminants had already been imposed after the first cases of "bovine spongiform encephalopathy" (BSE; "mad cow disease") in 1990. This ban was extended to cover all livestock in 2001. However, no further cases of mad cow disease have occurred for two years. For a few producers of slaughterhouse by-products (which includes meat and bone meal) this is sufficient justification to demand at least a partial relaxation of the ban on feeding meat and bone meal to animals. However, as the Swiss Federal Veterinary Office insists, sounding the all clear would be out of place. To keep BSE under control, it will probably be necessary to maintain the meat and bone meal ban for years to come.
- Sigurdson et al. De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis. Proceedings of the National Academy of Sciences, 2009; 106 (1): 304 DOI: 10.1073/pnas.0810680105
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