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Putting Prions to Work

By Sean Henahan, Access Excellence

lindquistChicago, IL (1/28/00)- Prions, the villainous protein-like particles associated with BSE, also known as "Mad Cow Disease", and its human counterpart, Creutzfeld-Jakob Disease (CJD), now appear to offer promise as a valuable tool for molecular biological research.

left: Susan Lindquist, Ph.D, University of Chicago

Prions are a kind of stray protein found in living tissue. They contain no nucleic acid (DNA or RNA) of their own. A prion consists of a single molecule containing about 250 amino acids. They are abnormal variants of proteins that occur normally in cells, such as human brain cells. When abnormal prions enter the body, they are able to convert their normal counterparts into more of the abnormal forms, beginning the process of neuronal cell destruction that manifests as prion disease. The difference between the normal and abnormal proteins does not lie in the sequence of their amino acids, but rather in their folding. The abnormal prion proteins are folded in a way that allows them to avoid normal protease degradation. As a result they begin to form clumps or aggregates, literally eating holes in the infected brain.

Now, researchers have shown that these same characteristics that make prions so dangerous may also be used in the lab to study genes and protein expression. Working with yeast prions and rat cells, researchers at the University of Chicago demonstrated a way to attach a prion to a normal protein so as to give it prion-like characteristics. Moreover, these prions are then passed on to subsequent generations of cells, while leaving the cells; DNA unchanged. The researchers alos observed that the misfolded parts of prions, are modular and can be swapped from one prion to another. The scientists induced the experimental novel prion to switch from its dysfunctional to its functional state and back again. This suggests an entirely new method for studying proteins, in which researchers could study the role of a particular protein by inducing it to become a prion.

"We've discovered a method to create novel prions which ultimately can have a lot of applications," said Susan Lindquist, Ph.D., the Albert D. Lasker professor of molecular genetics & cell biology and Howard Hughes Investigator at the University of Chicago. "Once the prion part misfolds it entices other proteins of the same kind to fold incorrectly and they can clump together. The functional part may still be active. But if its job needs to be done in a particular place, it can't get there because its stuck."

"The fact that these prion domains proved so modular and transferable, as revealed in these papers, proved quite a surprise. Since prions such as Sup35 had evolved to have the same general structure for many millions of years, one might have expected their different domains to have evolved together to influence one another. This modularity suggests that as species evolved, other proteins might have picked up these prion domains and become genetic elements. If they did, this kind of protein inheritance pattern could have had an important effect on the process of evolution," said Lindquist.

Prions violate the the "central dogma" of biology. All other known life forms pass along traits via their DNA, or in the case of some viruses, via RNA. The 'dogma' requires a process involving replication of DNA, transcription of the message into RNA, and translation of the RNA's message to form proteins, the building blocks of cells, tissues, organs and whole organisms. Prions, in contrast, bypass this entire process, direct the refolding of normal proteins just by direct contact.

The research appeared in the Jan. 28, 2000 issue of Science. A related article appears in the January 2000 issue of the journal Molecular Cell

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