For more than a decade, researchers have seen prions, an odd class of proteins that can modify the shape of other nearby proteins, as nothing but a liability. Genetically engineered mice that didn't produce prions seemed to have only minor problems, such as sleeping disorders. However, a 1993 experiment showed that the same mice were also immune to the mouse-form of bovine spongiform encephalopathy, or mad cow disease. These apparently unnecessary biological oddities were suddenly at the root of one of the most mysterious diseases known to man.
A new study published in the February 14th issue of the Proceedings of the National Academy of Sciences (PNAS) indicates that these apparent protein harbingers of mad cow could also serve a primary role in stem cell activity.
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The modus operandi of bacteria and viruses—the usual suspects of sickness—is written out in their DNA and RNA. This means that they behave in determinable and, therefore, theoretically treatable ways.
Prion-based disease, on the other hand, spreads by domino effect. One malformed prion somehow causes all those around it to take on the same dubious shape. There is no destructive life form, just an ever-spreading biochemical wildfire.
"Prion disease is entirely different from anything that we're used to looking at, and we don't really have a good idea of how to even begin to approach it," said Andrew Steele, a researcher at the Whitehead Institute in Cambridge, Mass.
For a long time, it looked like the oddly behaving prions were just a weak-spot evolutionary anachronism—the molecular version of the appendix, Steele said. But in a paper published online in late January, also by PNAS, Steele and fellow researcher Chengcheng Zhang showed otherwise. Mice that don't produce prions also lose their ability to regenerate adult stem cells in their bone marrow. The effect wasn't noticeable until the researchers reduced the marrow through radiation therapy similar to what a cancer patient experiences.
This examination of the prion's métier has been refocused on the brain in the most recent study. Steele and Jason Emsley from Massachusetts General Hospital observed how the presence of prions affected the speed at which neural precursor cells differentiated into the brain's component neurons. The precursor cells of mice with no prions took a very long time to differentiate, while those in mice who hyper-express prions differentiated very quickly.
The research suggests that the proteins, which reside on the surface of cells, play a roll in signal transduction—the process by which cells communicate and work together, according to Vilma Martins, a neural prion researcher at the Ludwig Institute for Cancer Research in São Paulo, Brazil. Martins' own research has led her to believe that prions are probably involved in many signalling processes, including a "survival signal" that stops cells from destroying themselves when they become just slightly damaged.
"The way that prion disease spreads shows that these proteins have some really remarkable properties," said Martins. "It's a good bet that our body puts those properties to good use."
How this role as a signalling protein plays into the disease that is caused by the prions' Dr. Jekyll and Mr. Hyde qualities still isn't understood, however. It is possible that malformed prions somehow cause burgeoning stem cells to misform, resulting in the spongy appearance of the brain associated with mad cow, Martins said. Or it could simply be that the prions become inactive, allowing other damaging processes to set in.