Study supports idea prions can infect brains

Researchers say they finally have proof of a controversial theory on the cause of a fatal family of brain disorders that includes mad cow and chronic wasting disease.

They did so by creating the first synthetic prions, infectious agents devoid of any genetic material, and used them to inflict brain disease in mice.

If they are right – and at least a few skeptics remain unconvinced – their findings could settle a debate about the nature of human prion diseases, mad cow disease and chronic wasting disease in deer while providing insight into more common brain disorders such as Alzheimer’s and Parkinson’s.

All of those diseases involve misshaped proteins that clump in the brain. Understanding how those proteins are coaxed to adopt abnormal shapes will help scientists develop therapies that prevent the process.

“It’s the sort of proof that many of us have been looking for,” said Byron Caughey, a prion disease researcher with the National Institutes of Health.

“The results are tantalizing. If what they are seeing is real, it’s exciting.”

The researchers say their prions were purified to be free of any conventional microbe such as a bacterium, virus or any agent with DNA or RNA.

These protein-only molecules were turned into larger protein structures known as amyloid fibrils and then injected into the brains of special laboratory mice.

Once inside the mouse brains, the prions began making copies of themselves, eventually causing the animals to come down with what is believed to be a new strain of brain disease in the same family of disorders that includes mad cow disease, chronic wasting disease in deer and Creuztfeldt-Jakob disease in people.

The scientists, whose work appears today in the journal Science, say the experiment provides “compelling evidence” for the so-called prion hypothesis. The theory holds that such diseases are caused by a rogue agent that replicates itself in the brain by inducing normal prion proteins to adopt its misfolded shape.

“That’s what we showed,” said Giuseppe Legname, the study’s lead author and an assistant professor of neurology at the University of California, San Francisco. “It is pure protein, nothing else.”

The prion hypothesis was presented in the early 1980s by UCSF scientist and Nobel Prize winner Stanley Prusiner, the senior author on the Science paper. Prions, he says, are chemically identical to normal prion protein but are able to induce disease because they have a slightly different three-dimensional shape.

“It’s been a controversy for a long time,” said Andrew Monjan, chief of the neurobiology of aging branch of the National Institute on Aging, part of the NIH, which co-funded the study. “Certainly it was a shift in thinking about how infections can take place.”

Monjan said the study largely proves the hypothesis, although his assessment of the experiment left a little wiggle room.

“It basically gives more validity to the prion hypothesis,” he said. “Until it is disproved, I think it’s a viable demonstration that the prion theory is correct.”

Potential flaws However, some researchers in the field who have not bought into the theory say the experiment had a couple of potential flaws.

It was possible that the synthetic prions used in the experiment were contaminated by an undetected viral agent, although the UCSF researchers say they went to great lengths to eliminate that possibility.

“I think there is a serious issue with contamination,” said Laura Manuelidis, a longtime critic of the prion theory and a neuropathologist at Yale University. “I think it (the study) is very misleading.”

Earlier this year, Frank Bastian, a professor of neuropathology at Tulane University, said he found an unusual bacteria known as spiroplasma in brain tissue samples from people and animals with various prion diseases. However, no one else has duplicated his research.

Others say the UCSF experiment was far from being straightforward and involved several complicated steps.

Manufactured proteins The synthetic prions were not produced merely by mixing amino acids. Instead, they were manufactured by genetically engineered E. coli bacteria, similar to the process now used to make another protein, human insulin.

The prions then were folded into larger amyloid fibrils, protein structures that are akin to the misfolded proteins that are the hallmark of Alzheimer’s disease.

The next step was to inject the fibrils into transgenic mice, rodents that were genetically engineered to overproduce a type of normal prion protein in their brains.

At first nothing happened and the experiment was almost abandoned. But more than a year later the mice began showing symptoms of a neurological disorder. Between 380 days and 660 days after they were injected, all seven of the mice got sick.

The researchers then used brain extract from the diseased mice to inoculate more mice, both transgenic and normal types. This time the brain illness showed up in 90 to 150 days.

One concern is that the transgenic mice used in the experiment were more susceptible to spontaneously generated prion disease.

A more direct and definitive experiment would be to inject the prions directly into the brains of normal mice, said Pierluigi Gambetti, director of the National Prion Disease Pathology Surveillance Center and a professor of neuropathology at Case Western Reserve University.

Still, he said, the research is convincing.

“It’s an extremely important contribution,” he said. “It nails down the issue.”

In addition, the research will help scientists better understand more common brain diseases such as Alzheimer’s, which also involve misprocessed proteins, and develop treatments such as vaccines, Gambetti said.

“If you learn how to treat Alzheimer’s, you may learn how to treat prion diseases and vice versa,” he said.

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