Look, Ma, No DNA!

In a finding that supports both an alternative mode of inheritance and the leading theory behind the mysterious "mad-cow" disease and Creutzfeldt-Jakob disease, Susan Lindquist and colleagues at the U of C Medical Center have shown that a cell trait can be propagated by a faulty protein, without any DNA or RNA serving as the genetic blueprint. Reporting her results in an August Science, Lindquist described the discovery as "genetics without DNA."

Lindquist's team found that an improperly folded protein in yeast cells clumps together and then--in a process much like the "seeding" of a crystal--corrupts other, healthy molecules of the same protein, causing them to do likewise. When the cell divides, the corrupt protein is apparently transmitted to both daughter cells, where the process is repeated. Because a protein's biological function depends on its three-dimensional shape, the corrupt species can confer a different trait from the identically composed, normal version.

"We think this is a mechanism of inheritance that people haven't realized existed," says Lindquist, a professor of molecular genetics & cell biology who studies the regulation of genes in fruit flies and yeast. "We've shown that a change in the shape of a protein can perpetuate itself and be passed to other cells, without a change in DNA or RNA. It goes against our notions of inheritance, that DNA or RNA is the only genetic material."

The new finding offers direct, physical evidence supporting protein-based inheritance, thus strengthening the "prion hypothesis" of the cause of such mammalian neurodegenerative diseases as sheep scrapie, mad-cow disease (bovine spongiform encephalopathy), and the kuru disease of the Papua New Guinea tribes--an affliction believed to be spread through ritual cannibalism. While some blame these diseases on DNA- or RNA-bearing viruses, others think the cause is infectious protein particles called prions: normal, cellular proteins that supposedly change their shape and then mold other protein molecules into the same, sickly altered form.

No one's yet proven that prions--a heresy to some--are real. But Lindquist, with research associates Maria Patino and John Glover and graduate student Jia-Jia Liu, has now shown that prion-like elements exist--at least in yeast.

Her team focused on a yeast protein called sup35, part of the normal yeast's machinery for making all proteins in the cell. In certain strains--with DNA that's apparently identical to the normal strain--the sup35 protein doesn't work. In the past, though, a link between inheritance of the mutation and a change in sup35 hasn't been found.

By separating the cell contents in a centrifuge, the Chicago researchers demonstrated that the protein is dispersed evenly in normal yeast cells but clumps together in affected strains--a phenomenon also observed in mammalian diseases where prions are suspected. To tie the clumping to heritability, Lindquist and company attached a fluorescent tag to the sup35 molecule, allowing them to observe affected cells converting newly-synthesized protein into the defective, clumping form.

The mutant yeast pose no risk to consumers of bread or beer--the sup35 protein is unrelated to the proteins hypothesized as mammalian prions. Still, the U of C researchers think that analysis of the prion-like yeast molecule and related proteins that help it fold may lead to new ways to treat certain neurodegenerative diseases.

Indeed, the power of the prion hypothesis, some biologists believe, is that it blurs the distinction between infection and inheritance. In the mammalian brain, where mature cells do not divide, prions are thought to pass between cells to transmit a disease; in yeast, they produce heritable changes from one generation to the next.

Prions' role in disease may remain unproven, but they do seem to exist widely in nature. And that, says Lindquist, is among the most important implications of her group's work.

Written by Andrew Campbell

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