Scientists have known for decades that infectious proteins called prions cause some neurodegenerative diseases, such as mad cow or its human variation, Creutzfeld-Jakob disease. When these proteins fold normally, they often play beneficial roles in biology; misfolded, however, they form tangled fibrils called amyloids that cause disease. What’s more, the misfolded prions have the bizarre ability to prompt other proteins to misfold. The result is the impairment or death of previously healthy cells.
Prions secrets: Arrays of protein segments, such as the one shown above, helped researchers pinpoint regions of prions that cause other proteins to change their shape.
Scientists have had little idea of how prions cause such destruction. Now researchers at the Whitehead Institute for Biomedical Research have identified short stretches of the proteins that control how prions form, replicate, and cross between species. These small but critical regions of the proteins may be responsible for prions’ infectious nature–and scientists may be able to use them to create treatments for prion diseases. “It may be possible to design drugs to specifically target these regions and inhibit prion formation,” says Peter Tessier, the postdoc who did the study, published online in Nature.
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Working in the lab of Whitehead member and MIT biology professor Susan Lindquist, Tessier created arrays of overlapping segments of a nontoxic prion protein from baker’s yeast. Exposing these arrays to the full prion domain of the protein, he identified a small region of the protein that recruited the prions to misfold into amyloid structures. Tessier called the region, which makes up less than 10 percent of the protein, a “recognition element.”
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Tessier found a similar recognition element when he repeated the experiment with prions from the fungus responsible for yeast infections in humans. However, prions from baker’s yeast could not induce prions from the pathogenic fungus to misfold, and vice versa–that is, the prions maintained a strict species barrier. In contrast, the prion protein involved in mad cow and transmissible Creutzfeld-Jakob can infect both cattle and humans, crossing between species.
An artificial yeast prion assembled from pieces of both prions by another lab had demonstrated the ability to cross the yeast species barrier, but earlier studies had not shown how. Using his protein arrays, Tessier showed that the artificial prion contains the recognition elements from both species. He believes that natural prions may often contain more than one recognition element as well, perhaps explaining the ability of some prions to cross species.
Although Tessier is excited about these findings, he cautions that there is still a great deal that researchers don’t know about these recognition elements. For instance, although the types of amino acids within them seem to be important, there is no obvious similarity between the sequences of the two elements they’ve so far identified. “Generally, we don’t understand what’s important about these sites,” Tessier says.
In addition, although it seems likely that similar mechanisms play a role in the formation of mammalian prion amyloids, proving this may be difficult, since the mad-cow protein is much harder for researchers to work with than yeast prions are. But Tessier has already begun the effort to extend his technique and understanding to pathogenic prions.
