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.

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.”

Scientists have shown how a family of “limpet-like” proteins play a crucial role in repairing the DNA damage which can lead to cancer.

They hope the finding could pave the way for a new type of drug which could help kill cancer cells, and promote production of healthy replacements.

The proteins seem to have a remarkable ability to zero in on damaged areas.

The breakthrough, uncovered independently by two teams, appears in the journal Nature.

The family of Small Ubiquitin-like Modifier (SUMO) proteins track down sites in the body where DNA damage has occurred.

They attach themselves to normal proteins, and guide them in to fix the genetic faults.

Using this method, the proteins are even able to repair double strand DNA breaks – the most severe type of DNA damage.

When their work is done, the proteins detach themselves and move on.

Breast cancer gene

One of the study teams was able to follow this process of repair taking place on the BRCA1 gene, which, if damaged, is associated with a very high risk of breast cancer.

SUMO was shown to attach to the damaged gene, and switch it back on – helping prevent breast cancer forming.

Researcher Dr Jo Morris, from King’s College London, said: “This new insight is the first step towards developing drugs which may protect normal cells from the side effects of chemotherapy, or improve the effectiveness of current breast cancer treatments.”

Dr Lesley Walker, of Cancer Research UK, which part-funded the study, said: “DNA damage, particularly double strand DNA breaks, are a fundamental cause of cancer and we know that people who have mutations in the BRCA1 gene have a higher risk of developing some kinds of cancer.

“Discovering that these limpet-like proteins play such an important role in repair may provide new opportunities to stop cancer from growing.”

But she added: “This is an extremely complex and intricate biological process so it may be many years before we can use this knowledge to safely intervene and help treat cancer patients.”

In these diseases, proteins in the body react with sugars in a process called glycation. This modifies the protein’s function and can trigger complications such as inflammation and premature aging.

The team at Bath, led by Dr Jean van den Elsen and Dr Tony James, has developed a technique that can detect glycated proteins and could in the future be used for diagnosing a whole range of diseases in patients.

They used a technique called gel electrophoresis, where samples are put into a thin gel layer and an electric current is applied. The gel acts like a molecular sieve, sorting proteins from the samples according to their size and shape, allowing scientists to identify whether specific proteins are present in the blood.

For this study, the researchers have patented a new type of gel electrophoresis, which uses boronic acid to distinguish between the glycated and unmodified proteins.

Dr Tony James from the University’s Department of Chemistry explained: “Not all sugars are ‘bad’ – in fact many proteins contain beneficial ‘good’ sugar units.

“However, some sugars can be ‘bad’ and cause complications in diseases such as Alzheimer’s and diabetes.

Dr Jean van den Elsen, from the University’s Department of Biology & Biochemistry, said: “Our method specifically recognises these ‘bad’ sugars in the presence of the ‘good’ sugars and as such is an excellent diagnostic tool.”

PhD student Marta Pereira Morais added: “We believe our method will also aid the development of new drug based therapies for these diseases.”

Whilst the technique has only been assessed in the lab at present, the researchers say it has the potential to be developed into a test for these conditions in patients.

Dr James added: “Currently there is no blood test for Alzheimer’s disease.

“If we can develop this technique into a test, doctors could potentially diagnose patients at an early stage before their symptoms show up in a brain scan.”

The method could also be used to diagnose diabetes, which also leads to elevated levels of glycated proteins in the blood.

Dr van den Elsen said: “Whilst there are other methods of detecting diabetes, this will be an excellent way to measure the level of this glycation damage.”

The importance of the technique has been recognised by publication in the scientific journal Proteomics and by the University which has patented the method.

The project was funded from a number of sources including the University’s Enterprise Development Fund (EDF), the Biotechnology & Biologcial Sciences Research Council and the Royal Society.

The team is now looking for industrial collaborators to help develop the technique further with the aid of the University’s technology transfer centre, Bath Ventures.

Scientists searching for the secrets of how calorie-restricted diets increase longevity are reporting discovery of proteins in the fat cells of human volunteers that change as pounds drop off.

The proteins could become markers for monitoring or boosting the effectiveness of calorie-restricted diets – the only scientifically proven way of extending life span in animals. Their study appears online in ACS’ Journal of Proteome Research.

Edwin Mariman and colleagues note that scientists have long known that sharply restricting intake of calories while maintaining good nutrition makes animals live longer and stay healthier. Recent studies suggest that people may gain similar benefits. But scientists know little about how these diets work in humans, particularly their effects on cells that store fat.

The new study focused on proteins in abdominal subcutaneous fat cells from a group of overweight people before and after they went on a five-week-long calorie-restricted diet. The volunteers each lost an average of 21 pounds. Scientists identified changes in the levels of 6 proteins as the volunteers shed pounds, including proteins that tell the body to store fat.

These proteins could serve as important markers for improving or tracking the effectiveness of therapies involving calorie-restricted diets, they say.

Scientists fed a mixture of amino acids to brain-damaged mice. The drinks restored the right balance of brain chemicals in their brains which returned their learning capacity returned to normal levels.

Head researcher Dr Akiva Cohen, from The Children’s Hospital of Philadelphia in the US, said if the results were reproduced in humans, patients with traumatic brain injuries could be given the amino acids in a drink.

Amino acids are the building blocks of proteins and especially found in beans, nuts and meat.

The mice drank leucine, isoleucine and valine – known as branched chain amino acids (BCAAs) – in their water.

These amino acids are vital for the creation of two brain chemicals which play a key role in the function of nerves.

These neurotransmitters work together to keep brain activity in balance. Glutamate excites neurons, stimulating them to fire, while GABA inhibits them.

If neurons are too excited or not excited enough, the brain does not function properly.

This often occurs after a traumatic brain injury common in road accidents or on the battlefield.

Previous research had suggested that people with severe brain injuries showed improvements in their mental capabilities after being injected with BCAAs.

Scientists tested the effect of brain injuries on the ability of mice to remember an electric shock.

A week after receiving a mild shock in a recognisable cage, normal mice tend to ‘freeze’ when placed in the same surroundings.

This is a fear response showing that they anticipate another shock after remembering what happened the first time they were in the cage.

Brain injured mice demonstrated fewer freezing responses, a sign that their learning was impaired.

When the brain-injured animals were given water containing the amino acid cocktail, their performance in the test was the same as that of normal mice.

The findings were published online today in the journal Proceedings of the National Academy of Sciences.

Dr Cohen said: ‘We have shown in an animal model that dietary intervention can restore a proper balance of neurochemicals in the injured part of the brain, and simultaneously improves cognitive performance.’

Examination of slices of tissue from the hippocampus – the brain’s memory centre – showed that BCAA restored the normal balance of neural activity in injured mice.

Providing BCAAs in the diet may prove more effective than injecting them, Dr Cohen said.

A large dose injected straight into the bloodstream could flood the brain and have a more limited effect.

New researchers done in Kimmel Cancer Center at Jefferson have found a novel mechanism by which drugs block HIV-1 from entering host cells. Cellular invasion by HIV-1 requires the concerted action of two proteins on the viral surface: gp120 and gp41.

The function of gp41 is to get the viral contents into the interior of the host cells. This requires the association of two distinct regions of gp41 called N-HR and C-HR. Anti-HIV-1 agents known as fusion inhibitors target the N-HR or C-HR and disrupt their association, which prevents the virus from entering into the host cell.

One drug that works like this is Fuzeon (Roche), and there are other agents in the pipeline.But blocking the N-HR/C-HR association is not only mechanism by which fusion inhibitors prevent HIV-1 entry, according to Michael Root, M.D., Ph.D., assistant professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University. The inhibitors also induce irreversible deactivation of gp41.

“After these drugs bind, they seem to shuttle gp41 into a dead conformation from which the protein cannot recover,” Dr. Root said. “Importantly, the speed of this drug-induced deactivation greatly influences how potent a drug is at preventing HIV-1 infection.”

When the inhibitors bind to the gp41 C-HR, the protein rapidly deactivates before inhibitors have time to dissociate. But when the inhibitors bind to the gp41 N-HR, deactivation takes a very long time, and many inhibitors can readily unbind. To potently inhibit HIV-1 entry, a C-HR targeting fusion inhibitor can have a relatively low affinity, but an N-HR targeting fusion inhibitor must bind extremely tightly.

A major drawback to using Fuzeon and related drugs that target N-HR is the rapid emergence of HIV-1 strains resistant to the drugs. Dr. Root’s study suggests that the resistance phenomenon is related to the slow speed of gp41 deactivation induced by these fusion inhibitors.

HIV-1 appears to have more difficulty developing resistance to drugs that can remain bound to gp41 for much longer than gp41 takes to deactivate, even if the drugs are no more potent than Fuzeon against the original HIV-1 strain. Armed with this knowledge, Dr. Root and his team have developed a new strategy to improve the antiviral activities of N-HR-targeting fusion inhibitors.

These unexpected properties of HIV-1 fusion inhibitors are a consequence of the short time interval these drugs have to work. The N-HR and C-HR are only accessible to drug binding in a short-lived “intermediate state” that occurs right before N-HR/C-HR association.

Most pharmaceutical agents bind targets that exist for long times, but a growing class of drugs target similar, short-lived intermediate states. These drugs include local anesthetics, antibiotics and immunosuppressive agents used in clinical practice. The results of this study might also be extended to understand the activities and limitations of these drugs.

Now scientists have created tiny particles in the laboratory that mimic those good carriers, scooping up the cholesterol before it can grow into dangerous deposits of plaque. The surfaces of these new particles are coated with fats and proteins so they can bind tightly with the sticky cholesterol to transport it through the bloodstream.

The particles may someday be important in treating cardiovascular disease, said Dr. Andre Nel, chief of the division of nanomedicine and director of the Center for Environmental Implications of Nanotechnology at the University of California, Los Angeles.

“Researchers have endowed these artificial particles with the same properties as natural particles that circulate in the blood,” called high-density lipoproteins, or HDL, he said. The artificial carriers can clean up sites where plaques can otherwise rupture, leading to strokes and heart attacks.

The particles may be useful not only in cardiovascular therapy, but also in diagnosis. The researchers have put gold and other metal cores at the center of the particles, Dr. Nel said, so that they show up well in medical imaging. Such imaging could be used, for example, to monitor plaques as they build up in blood vessels.

At the Chicago campus of Northwestern University, artificial HDL nanoparticles have been designed by Dr. C. Shad Thaxton, an assistant professor in the urology department, and Chad A. Mirkin, a professor and director of the International Institute for Nanotechnology at the university’s Evanston campus They have founded a company, AuraSense, to commercialize the technology.

The Northwestern researchers replaced the fatty core found in natural HDL with gold nanoparticles, Dr. Mirkin said. “The gold core serves as a scaffold for attaching molecules that are the same as those on the surface of naturally occurring HDL,” he said. “We have demonstrated that our synthetic version of HDL binds cholesterol very tightly, not only in the laboratory, but in animals.”

The group has done a pilot study in animals and will soon begin a larger study, also involving animals, Dr. Thaxton said

At the Mount Sinai School of Medicine in Manhattan, Willem J. M. Mulder, an assistant professor of radiology and gene and cell medicine, and his research group have developed HDL-like nanoparticles intended primarily for imaging and diagnosis. The particles have centers of gold or other materials, Dr. Mulder said, depending on the type of imaging to be used.

“One of our interests is in the imaging of the biological processes in atherosclerosis,” the hardening of the arteries caused by plaques, he said.

Gold nanocrystals show up well in one type of imaging, called computed tomography, he said, and iron oxide nanocrystals work well with magnetic resonance imaging.

The research of the Northwestern and Mount Sinai groups may one day benefit people who develop deposits of atherosclerotic plaque, said Dr. Gregory M. Lanza, a professor of medicine at the School of Medicine at Washington University in St. Louis.

“Both of these groups have shown that this HDL mimic can adsorb cholesterol,” he said. One day, the particles like those created by the groups may be included in therapies for heart disease, he said. “They may become part of good anti-atherosclerosis management, along with diet, nonsmoking and statins,” drugs that interfere with the synthesis of cholesterol.

BUT for that to happen, cautioned Dr. Nel at U.C.L.A., more study will be needed. “We will have to find out what happens when the gold nanoparticles accumulate in the body,” he said. “This is a problem for treatment of chronic diseases where you administer materials over a long time.”

Vincent M. Rotello, a professor of chemistry at the University of Massachusetts, Amherst, who does nanoparticle research, agreed. “Right now, nanoparticles are great for diagnostic and acute therapeutics,” he said, but issues lie ahead that must be solved before the particles can be prescribed.

“Gold is nontoxic,” he said. “But it does build up. We don’t know what the effects of the buildup might be.” Smaller particles are excreted, he said. But larger particles may accumulate in the liver. Dr. William O’Neill, executive dean for clinical affairs at the Miller School of Medicine at the University of Miami, welcomed the artificial particles.

“If we can prove they don’t have side effects, we could give them as a drug, causing plaque in the coronary arteries to shrink,” he said. “It could revolutionize cardiology.”