Scientists have located two possible receptors for the so-called prion protein (PrP) believed to be at fault in fatal neurological conditions such as "mad cow disease," Creutzfeldt-Jakob disease in humans, and scrapie in sheep. Many researchers believe PrP causes disease when it misfolds and then triggers other proteins to do likewise, eventually killing brain cells. But--although normal PrP is present in the brains of all vertebrates examined so far--no one knows what it does in healthy cells.
In the December issue of Nature Medicine, independent teams in Germany and Brazil describe two proteins that may help researchers solve that mystery and could provide clues to exactly how the rogue proteins wreak their havoc. Ricardo Brentani, a molecular biologist at the Ludwig Institute for Cancer Research in São Paulo, Brazil, and his colleagues relied on a technique known as complementary hydropathy to locate a protein that interacts with PrP. The idea is that complementary strands of DNA encode proteins that bind to each other. So the scientists constructed a protein fragment based on a DNA sequence made up of bases complementary to those of the PrP gene, and then developed an antibody to the protein fragment. When applied to neurons in cell culture, the antibody locked onto a protein on the cell surface. This surface protein, which has not yet been named, also binds to normal PrP both in protein assays and in cell cultures.
The newfound protein might eventually help patients who suffer from the untreatable prion diseases: When the group mixed their artificial protein fragment with a fragment of the PrP protein that usually kills neurons in petri dishes, the mixture killed only half as many cells as the prion fragment alone. The new protein seems to bind to its evil sibling, perhaps preventing it from entering cells, Brentani says.
To find the second receptor protein, molecular biologist Stefan Weiss of the University of Munich in Germany and his colleagues used a technique called a two-hybrid yeast screen, which turned up another protein on the cell surface called the laminin receptor precursor (LRP). The team reports that LRP is present in higher levels in organs that are affected by prion diseases, including the brain, spleen, and pancreas. In addition, the protein seems to be more prevalent in diseased tissues with high concentrations of the deadly form of PrP.
It's not yet clear if the proteins are related, or how many other PrP receptors might exist. But any receptor could be "a new target for disrupting the life cycle of prions," says Weiss. Other researchers are excited by the find. "Any protein that interacts with PrP is likely to be interesting," says cell biologist David Harris of Washington University in St. Louis, because it may be involved in both the protein's normal function as well as the disease-causing conversion.