The two faces of prion proteins

When the nefarious Mr. Hyde takes his own life, the good Dr. Jekyll is also killed.

Scientists are adopting the reverse approach for halting the protein behind prion diseases such as Creutzfeldt-Jakob and mad cow. By targeting the harmless version of the brain protein whose evil alter ego brings on disease, researchers have prevented the bad version of the protein from continuing its rampage in the brains of infected mice. The results are reported online July 14 in Proceedings of the National Academy of Sciences.

The approach of killing Jekyll to get Hyde is very promising, comments biochemist Sina Ghaemmaghami of the Institute for Neurodegenerative Diseases at the University of California, San Francisco. The sinister version of the protein comes in several slightly different forms, making it hard to develop a single attack strategy, Ghaemmaghami says.

Led by neuroscientist Giovanna Mallucci of University College London, researchers delivered bits of attack RNA to interfere with production of the normal version of the prion protein. In animals who have prion disease, this protein somehow gets converted into a dangerous form, which then travels through the brain, coaxing other good versions of the protein to go bad.

The bad versions of the protein then clump together, a process that damages cells, although scientists aren’t exactly sure how.

“No one knows what the toxic entity is — that’s the black box,” says Mallucci.

It’s also a mystery how prions replicate — they seem to do it without DNA — and they are difficult to kill.

Using bits of RNA that interfere with protein production has potential as a therapy for treating many neurodegenerative diseases, but those therapies are a ways off, says Ghaemmaghami. In the new study, researchers injected the interfering RNA, packed in a lentivirus, into the hippocampus of rodents already given a diseased version of the protein. Treated animals lived longer and had fewer symptoms of prion disease.

But getting therapeutic molecules into the human brain is another story, especially molecules as big as RNA. “The brain is just about the hardest place to get into,” Ghaemmaghami says.

In a separate study, researchers have come closer to understanding what PrP, the innocuous Dr. Jekyll version of the prion protein, does for a living. The PrP protein is found in most brain cells, but its function remains a mystery. Mice engineered to not have the PrP protein appear relatively healthy. The slight differences scientists have noted is that PrP-free mice don’t perform quite as well as their normal counterparts on some learning and memory tasks and also don’t recover as well from seizures or strokes.

To investigate the role of regular PrP, Gerald Zamponi and colleagues at the University of Calgary in Canada looked at communication among the brain cells of PrP-free mice. When the nerve cells received the messenger molecule known as glutamate, they went into hyperactive mode, repeatedly firing as if the message had been shouted at them, says Zamponi. These overexcited cells were more likely to die because of this overactivation, the scientists report in a recent Journal of Cell Biology.

Normal PrP protein might function to block some NMDA receptors and thereby prevent overexcitement of certain neurons, says Zamponi.

The researchers also removed magnesium from the cells. Magnesium usually blocks some of the receptors that catch the NMDA messages. Without it, the brain cells went into seizure mode, further evidence that the PRP-free mice were super-sensitive to NMDA.

The PrP protein seems to have emerged late in vertebrate evolution—there is no version that scientists can scrutinize in critters like yeast and fruit flies. While it is too early to conclusively identify its role, investigating what the good version of the protein does has merit, says UCSF’s Ghaemmaghami.

After all, that’s how the good Dr. Jekyll’s friends learned the origin of the deadly Mr. Hyde.