advertisement-vertical Download Proto magazine app
Social Icons
UPDATE //

Progress With Prions

New research sheds light on the mystery of prions: misfolded proteins that promote a lethal chain of events.

BY D.T. Max // Fall 2007
icon-pdfpdf icon-printprint
share: digg.com del.icio.us facebook.com
prion research

My article “In Pursuit of Prions” (Spring 2007) described the medical mystery that is prion disease: The time from infection to first symptom can be as long as 40 years; the disease leaves no trace of infection in the body; and the agent of infection seems to be neither virus nor bacterium. Rather, prions are ordinary cellular proteins. Unlike most proteins, each of which takes only one 3-D shape, prions appear to be able to form two: one normally folded shape and a misfolded one that causes disease (examples of which are bovine spongiform encephalopathy, or mad cow disease; kuru, which swept through Papua New Guinean tribes; and fatal familial insomnia, which has haunted one Venetian family for centuries). Misfolded prion proteins cause neighboring prions to misfold, spreading the “infection” and promoting a lethal chain of events.

Scientists haven’t known what triggers this effect, called conformational cascade. Indeed, as a result, some researchers have even doubted the existence of infectious prions, maintaining that a virus must be causing the disease. Now, new research might quiet the naysayers: By examining normal yeast prions, researchers at the Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research have pinpointed the source of infectivity in a small portion of a yeast prion protein. A group of amino acids—less than 10% of the entire molecule—misfolds and in turn causes adjoining yeast prions to misfold, effectively by altering the delicate balance by which their atoms attract and repel one another. 

This research yields two implications: If scientists could foil the activity of this amino acid group, known as a recognition element, they might be able to prevent prions from replicating. What’s more, the discovery seems to indicate that two species may not need to share similarly shaped prions—only similarly shaped recognition elements—for prions to cross the species barrier. A caveat: Yeast prions are quite different from those of mammals (for one thing, they don’t cause disease); researchers have begun to study whether the same recognition element appears in mammalian cells.

A more traditional approach to stopping infection also shows promise. Researchers at New York University injected mice with a vaccine against scrapie, a prion disease that occurs in sheep. After the mice were exposed to the disease, 30% of vaccinated mice remained symptom-free for 500 days, whereas all unvaccinated mice were dead within 300 days. At least one expert cautioned that researchers had not kept the vaccinated mice alive long enough to watch for signs of the disease. Nevertheless, the work pointed to the possibility of a vaccine that would be sensitive enough to distinguish between the victim’s native prions and the infectious ones. Most researchers have held that prion infections provoke no immune response because the body confuses the invading prions with its own.

Such discoveries not only edge closer toward cures for prion diseases but could also serve as an entry point into curing certain neurodegenerative, immune-system and metabolic diseases that share some of the symptoms of prion disease and leave misfolded proteins behind. It was a shock, then, when scientists at the University of Leeds found that normal prions might in fact protect against Alzheimer’s disease. In mice and lab-grown cells, a high level of normal prions had an inhibitory effect on the production of a protein called beta-amyloid, which builds the sticky plaques in the brain that characterize Alzheimer’s. Researchers found that healthy prions block an enzyme that cleaves a key Alzheimer’s protein; if the protein is intact, it cannot form the sticky plaques. The discovery suggests that a therapy mimicking the prion’s enzyme-blocking behavior might prevent Alzheimer’s.

Despite such leads, prion research is slow going. After Stanley Prusiner won a Nobel Prize for work in the field, he predicted a cure for prion diseases in five years. That was 1998.

Stat-arrow-green

In Pursuit of Prions

prion disease

Kuru, scrapie, a fatal form of insomnia—all caused by renegade proteins. Cure one and other, more familiar diseases may follow.

Protomag on Facebook Protomag on Twitter