Rehabilitating a Bad Protein
There is increasing evidence that prions - the biochemical epitome of evil - are also useful for something: For example, as a promoter of new brain wax. She is still surrounded by the aura of the enigmatic, mystical. And this has been the case since the 1960s, when Tikvah Alper and John Griffith speculated about their existence: the two British researchers claimed at the time that the sheep disease scrapie was not caused by bacteria or viruses, but simply by proteins. They were scorned and ridiculed for their outrage in doubting the claim to sole representation of nucleic acids as a hereditary substance - and quickly fell into oblivion.
Not so Stanley Prusiner, who gave the pathogens a name and was honored with the Nobel Prize for Medicine in 1997. Today, after a BSE crisis, hardly any molecular biologist still doubts that Prusiner - and thus also Alper and Griffith - were right: The prion protein PrP, as Prusiner called the mysterious protein, triggers a whole series of neurodegenerative diseases in humans and animal by folding other prion proteins in a misfolded form, effectively doubling itself. A fatal chain reaction with a fatal outcome.
But the mystery of the prions is far from being solved. On the contrary: if these proteins pose a deadly threat, why are they there at all? After all, they exist all over the place: Not only cows, sheep and humans have them - especially in the nervous system - even simple yeast cells can't seem to get by without them. So prions must be good for something, otherwise evolution would have eliminated them long ago.
To get to the bottom of the matter, researchers created genetically engineered mice that lacked PrP as early as 1993. But contrary to expectations, these mouse mutants were doing fantastic. They weren't any different from their normal counterparts, with one exception: they couldn't be afflicted with prion diseases.
At the end of 2003, the working group led by Nobel Prize winner Eric Kandel finally found the first indication of a positive role for the evil protein: they discovered a similar protein in the sea snail Aplysia, which appears to be involved in the mollusc's memory formation.
Two weeks ago, the researchers led by Cheng Cheng Zhang and Andrew Steele from the Whitehead Institute in Cambridge, USA, presented another surprising discovery: They discovered by chance that PrP plays an important role in maintaining blood-forming stem cells in the bone marrow.
Steele, who works in the lab of prion researcher Susan Lindquist, wasn't content with this finding and sought support in neighboring Boston. It was here, in Jeffrey Macklis' Harvard lab, that he found collaborators Jason Emsley and Hande Özdinler. The researchers worked with three different strains of mice: the first strain had the PrP gene knocked out, the second produced excess PrP, and the third, the control strain, was normal.
The more PrP there was, the faster neurons formed
(Andrew Steele) The scientists isolated neuronal progenitor cells from the embryonic brain tissue of their test animals – i.e. those early cell stages that can mature into both neurons and glial cells. In the culture dish, these cells also did what was expected of them: they developed into neural cells – albeit at different speeds. While the PrP-free progenitors took their time, the prion-rich versions didn't seem to be moving fast enough.
"The more PrP there was, the faster neurons formed," says Steele. "And the less there was, the longer the progenitor stage lasted."
So here's a helping hand from the bad protein: PrP helps produce new neurons in the brain. In contrast, it appears to be irrelevant for the supporting glial cells of the nervous system, which matured just as quickly with or without PrP.
However, the prion proteins still turned out to be expendable in the end. Because the PrP-containing mice were able to form new brain cells more quickly; however, the number of neurons ultimately remained the same in all three mouse strains.
The aura of the mystical is not yet completely lost to the prions.
