Eric Kandel, and colleagues have collaborated to show that proteins involved in normal cell processes can convert to a self-perpetuating, prion-like form to maintain memory, for example.

The results reinforce Lindquist's suggestion that prions may have evolved through the selective pressure of stress.

“I think the prion principle is a wonderful way to distribute information in a non-genetic way,” says Adriano Aguzzi, a prion expert at the University Hospital of Zurich in Switzerland, who credits Lindquist with building a convincing argument that the prion phenomenon is an alternate evolutionary pathway.

The 1982 discovery of prions by Stanley Prusiner, a biochemist at UCSF, was a stunning answer to a longstanding and stubborn problem: what was the mysterious agent responsible for transmissible spongiform encephalopathies (TSEs)—progressive, incurable, and lethal diseases that destroy nerve cells and leave a sponge-like trail of destruction?

The earliest known TSE was scrapie, an affliction of sheep. Other TSEs now known to be prion diseases are bovine spongiform encephalopathy (BSE, or mad cow disease) and some very rare but lethal neurodegenerative diseases in humans, including Creutzfeldt-Jakob disease (CJD), variant CJD, kuru, and familial fatal insomnia. These diseases have incubation periods measured in years.

The BSE epidemic of the 1980s and early 1990s killed 170,000 head of cattle and led to the slaughter of more than 4 million cows, mostly in England, before it subsided. During this epidemic, a form of BSE called variant CJD spread to humans who ate meat products from the infected herds. Mad cow disease killed about 200 people.

Scientists had determined that the agent carrying scrapie was very small and extremely hardy: it couldn't be inactivated by heat, ultraviolet radiation, or denaturing, which would destroy any genetic material used in reproduction.

Prusiner reported that the cause of scrapie was a novel infectious particle, which he dubbed a “prion,” consisting solely of misfolded proteins, devoid of genetic material. This was hard to swallow for many scientists, since even the smallest bacteria and viruses have some genetically encoded instructions for replication.

For years afterward, some skeptics rejected the “protein-only” model of prions, arguing that they must contain some genetic material that had escaped detection. A strong refutation of that view came in 2000 when Weissman at UCSF reported that he had created synthetic prions in a test tube directly from a pure yeast protein, Sup35.

To understand what makes a prion, recall that cells manufacture proteins by assembling chains of amino acids according to a “recipe” contained in a specific gene. Then the protein folds into a three-dimensional configuration like a complex piece of origami. If for any reason the protein fails to fold correctly, it may not work at all, or its function may be different from what was specified.

PrPSc, the scrapie prion isolated by Prusiner, is a misfolded form of a naturally occurring cell-membrane protein, PrP, which is expressed in nerve tissue and elsewhere in healthy people and many animals.

Photo: Matthew Septimus

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