Healthy prions protect nerves

After 20 years of research, scientists believe they have finally uncovered the normal function of prion proteins, which can cause deadly illnesses such as Creutzfeldt–Jakob disease (CJD) if they become incorrectly folded.

An international team of neuroscientists reports that, in mammals, the mysterious proteins help to maintain the myelin sheath that protects the body's nerves.

"This opens a new door to studying some of the many common neuropathy disorders — which lead to weakness or loss of sensitivity of limbs — where we don't know the cause," says prion expert Simon Mead at University College London's Institute of Neurology.

The authors suspect that their finding also applies to brain neurons. If so, this would have implications for treating deadly CJD and other transmissible spongiform encephalopathies. It could also offer a new way of looking at multiple sclerosis, an incurable disease caused by demyelination of nerves in the brain and spinal cord. The work is published online in Nature Neuroscience today1.

Long search

Several functions have been proposed for prions during the past couple of decades, but none has survived close scrutiny.

"The first mouse with knocked-out prion genes was made back in 1991," says Adriano Aguzzi at the University Hospital of Zurich in Switzerland, who led the new work. "We leapt on it, and studied it in every way we could think of — but never managed to find any obvious sign that lack of the prion was causing it harm."

In fact, at first glance, lack of prions seemed like a good thing because it made mice immune to prion infection.

But four years ago, Aguzzi started to think again about a generally overlooked 1999 paper2 by researchers in Japan that suggested the lack of prion protein caused the degeneration and demyelination of nerves outside the brain. He decided to undertake a thorough and systematic analysis of prions' effects on such peripheral nerves.

Together with his colleagues, he studied four different strains of mice lacking the gene for the prion PrPC. In every mouse they tested, regardless of strain, they found early evidence of myelin damage just six weeks after birth. By the age of two months, the nerves were extensively demyelinated, and the mice had become more sensitive to pain.

"Because there is no myelin damage at birth, we assumed prions are needed to maintain the quality of the myelin sheath, which diminishes throughout life," says Aguzzi. Accordingly, when the researchers re-introduced prion proteins specifically into nerves, the demyelination did not occur. Curiously, however, only variants of prion proteins susceptible to cleavage by enzymes were effective.

But no variant of prion protein was able to prevent demyelination when introduced specifically into the Schwann cells that surround and support peripheral nerve cells. "This surprised us," says Aguzzi, "since Schwann cells actually do the job of manufacturing fresh myelin."

Aguzzi concludes that when nerves' sheathes are suffering wear and tear, the nerves enzymatically cleave their prion proteins, releasing fragments that travel to Schwann cells, where they signal activation of myelin repair.

Brain effects

He also has a hunch, supported by preliminary data, that prion proteins will turn out to play the same part in supporting myelination in the brain. "So it is going to be interesting to see if prions play any role in demyelinating diseases that stem from the brain," he says.

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"Some potential treatments of CJD target the heathy prion protein," says Mead. "But if an absence of healthy prion protein was severely detrimental, then we might have to rethink this therapeutic approach."

Claude Carnaud, an immunologist working on prions at the INSERM research unit of the Pierre and Marie Curie University - Paris 6, says that some brain disorders that have been considered inflammatory in origin look like they may instead involve an absence of prions in the brain, at least in mice. "It will be very interesting to see if this also applies to multiple sclerosis," he says.