Prion proteins help to keep nerve cells well insulated.STEVE GSCHMEISSNER / SPL

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 PrP^C. 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.

“Treatment of CJD targets prion proteins, which are assumed to be doing the damage,” says Mead. “But if CJD did indeed turn out to be caused by absence of prions, then we would 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. 

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  References

  
  
  
  
  1. Bremer, J. et al. Nature Neurosci. doi:10.1038/nn.2483 (2010).
     
  2. Nishida, N. et al. Lab. Invest. 79, 689-697 (1999).

Prions ‘may keep nerves healthy’

Removing prion proteins led to a breakdown of the myelin sheath surrounding the nerve 출처 : BBC 00:02 GMT, Monday, 25 January 2010 http://news.bbc.co.uk/2/hi/health/8476093.stm Experiments on mice may help scientists understand the workings of the prion protein linked to brain disease vCJD. Swiss researchers say there is evidence that prions play a vital role in the maintenance of the sheath surrounding our nerves. They say it is possible that an absence of prions causes diseases of the peripheral nervous system. One expert said there was growing evidence that the prion had a number of important roles in the body. As well as the latest research in the journal Nature Neuroscience, other studies have indicated prions may protect us from Alzheimer’s disease or even play a role in our sense of smell. Most people started by focusing on prions in relation to a human disease, and have only recently started to examine what it normally does Professor Nigel Hooper, Leeds University The prion protein only came to the attention of scientists in recent years as they searched for the cause of vCJD – the human variant of BSE, or Mad Cow Disease. This degenerative and incurable brain condition is now thought to be caused by a “mis-folded” version of the prion. However, there is still little understanding of what the protein is supposed to do in its normal, healthy, form. Healthy prions The study, by scientists at the University Hospital in Zurich, looked at mice bred with fewer prion proteins. While these mice are known to be resistant to prion diseases equivalent to vCJD in humans, they showed a number of abnormalities, including a degeneration, later in life, of the peripheral nerve cells, and the protective myelin sheath which surrounds them. Peripheral nerves are those which link the limbs and organs to the central nervous system – the spinal cord and brain. Looking more closely, researchers examined the effects of removing the prion protein in both the nerve cells themselves, and the Schwann cells surrounding them, which are responsible for making the myelin sheath. While removing protein from the Schwann cells had no effect, taking it from the neurons led to a breakdown of the myelin and degeneration of the nerve cells. They said that the knowledge that prion protein played some role in the healthy upkeep of nerve cells could offer a new avenue of research into diseases affecting humans. However, scientists caution that it is too early to pick out a particular peripheral nerve condition which might correspond to the mouse experiments. Recent work Professor Nigel Hooper, from the University of Leeds, agreed that the role of the protein was not well understood. His own work, published in 2007, suggested that it might offer some protection from the development of Alzheimer’s disease. But he said this was unlikely to be the complete answer. He said: “Most people started by focusing on prions in relation to a human disease, and have only recently started to examine what it normally does. “There is some evidence that it could have a number of different roles, depending on its whereabouts in the body – a recent paper linked it to olfaction or the sense of smell.”