Neuroscience

Fresh insights into the protective seal that surrounds the DNA of our cells could help develop treatments for inherited muscle, brain, bone and skin disorders.

Researchers have discovered that the proteins within this coating – known as the nuclear envelope – vary greatly between cells in different organs of the body.

This variation means that certain disease causing proteins will interact with the proteins in the protective seal to cause illness in some organs, but not others.

Until now scientists had thought that all proteins within the nuclear envelope were the same in every type of organ.

In particular the finding may provide insights into a rare muscle disease, Emery-Dreifuss muscular dystrophy.

This condition causes muscle wastage and heart problems, affects only muscles, even though it is caused by a defect in a nuclear envelope protein found in every cell in the body.

Scientists say that the envelope proteins they have identified as being specific to muscle may interact with the defective nuclear envelope protein that causes Emery-Dreifuss muscular dystrophy, to give rise to the disease.

In a similar way, this may help to explain other heritable diseases that only affect certain parts of the body despite the defective proteins being present in every cell. The study also identified nuclear envelope proteins specific to liver and blood.

Some of these also interact with proteins in all cells that are responsible for other nuclear envelope diseases, ranging from brain and fat to skin diseases, and so may help explain why things go wrong.

Dr Eric Schirmer, of the University of Edinburgh’s Wellcome Trust Centre for Cell Biology, who led the study said: “Nobody could have imagined what we found.

The fact that most proteins in the nuclear envelope would be specific for certain tissue types is a very exciting development. This may finally enable us to understand this ever-growing spectrum of inherited diseases as well as new aspects of tissue-specific gene regulation.”

The findings build on previous research that showed proteins in the nuclear envelope are linked to more than 20 heritable diseases.

In a recently published study in the journal Biological Trace Element Research, Arizona State University researchers report that children with autism had higher levels of several toxic metals in their blood and urine compared to typical children. The study involved 55 children with autism ages 5–16 years compared to 44 controls of similar age and gender.

The autism group had significantly higher levels of lead in their red blood cells (+41 percent) and significantly higher urinary levels of lead (+74 percent), thallium (+77 percent), tin (+115 percent), and tungsten (+44 percent).  Lead, thallium, tin, and tungsten are toxic metals that  can impair brain development and function, and also interfere with the normal functioning of other body organs and systems.

A statistical analysis was conducted to determine if the levels of toxic metals were associated with autism severity, using three different scales of autism severity. It was found that 38-47 percent of the variation of autism severity was associated with the level of several toxic metals, with cadmium and mercury being the most strongly associated.

In the paper about the study, the authors state “We hypothesize that reducing early exposure to toxic metals may help ameliorate symptoms of autism, and treatment to remove toxic metals may reduce symptoms of autism; these hypotheses need further exploration, as there is a growing body of research to support it.”

The study was led by James Adams, a President’s Professor in the School for Engineering of Matter, Transport and Energy, one of ASU’s Ira A. Fulton Schools of Engineering. He directs the ASU Autism/Asperger’s Research Program.

Adams previously published a study on the use of DMSA, an FDA-approved medication for removing toxic metals. The open-label study found that DMSA was generally safe and effective at removing some toxic metals. It also found that DMSA therapy improved some symptoms of autism. The biggest improvement was for children with the highest levels of toxic metals in their urine.

Overall, children with autism have higher average levels of several toxic metals, and levels of several toxic metals are strongly associated with variations in the severity of autism for all three of the autism severity scales investigated.

(Image: Matthias Kulka / Corbis)

The origin of an innate ability the brain has to protect itself from damage that occurs in stroke has been explained for the first time.

The Oxford University researchers hope that harnessing this inbuilt biological mechanism, identified in rats, could help in treating stroke and preventing other neurodegenerative diseases in the future.

'We have shown for the first time that the brain has mechanisms that it can use to protect itself and keep brain cells alive,' says Professor Alastair Buchan, Head of the Medical Sciences Division and Dean of the Medical School at Oxford University, who led the work.

The researchers report their findings in the journal Nature Medicine and were funded by the UK Medical Research Council and National Institute for Health Research.

Stroke is the third most common cause of death in the UK. Every year around 150,000 people in the UK have a stroke.

It occurs when the blood supply to part of the brain is cut off. When this happens, brain cells are deprived of the oxygen and nutrients they need to function properly, and they begin to die.

'Time is brain, and the clock has started immediately after the onset of a stroke. Cells will start to die somewhere from minutes to at most 1 or 2 hours after the stroke,' says Professor Buchan.

This explains why treatment for stroke is so dependent on speed. The faster someone can reach hospital, be scanned and have drugs administered to dissolve any blood clot and get the blood flow re-started, the less damage to brain cells there will be.

It has also motivated a so-far unsuccessful search for ‘neuroprotectants’: drugs that can buy time and help the brain cells, or neurons, cope with damage and recover afterwards.

The Oxford University research group have now identified the first example of the brain having its own built-in form of neuroprotection, so-called ‘endogenous neuroprotection’.

They did this by going back to an observation first made over 85 years ago. It has been known since 1926 that neurons in one area of the hippocampus, the part of the brain that controls memory, are able to survive being starved of oxygen, while others in a different area of the hippocampus die. But what protected that one set of cells from damage had remained a puzzle until now.

'Previous studies have focused on understanding how cells die after being depleted of oxygen and glucose. We considered a more direct approach by investigating the endogenous mechanisms that have evolved to make these cells in the hippocampus resistant,' explains first author Dr Michalis Papadakis, Scientific Director of the Laboratory of Cerebral Ischaemia at Oxford University.

Working in rats, the researchers found that production of a specific protein called hamartin allowed the cells to survive being starved of oxygen and glucose, as would happen after a stroke.

They showed that the neurons die in the other part of the hippocampus because of a lack of the hamartin response.

The team was then able to show that stimulating production of hamartin offered greater protection for the neurons.

Professor Buchan says: ‘This is causally related to cell survival. If we block hamartin, the neurons die when blood flow is stopped. If we put hamartin back, the cells survive once more.’

Finally, the researchers were able to identify the biological pathway through which hamartin acts to enable the nerve cells to cope with damage when starved of energy and oxygen.

The group points out that knowing the natural biological mechanism that leads to neuroprotection opens up the possibility of developing drugs that mimic hamartin’s effect.

Professor Buchan says: ‘There is a great deal of work ahead if this is to be translated into the clinic, but we now have a neuroprotective strategy for the first time. Our next steps will be to see if we can find small molecule drug candidates that mimic what hamartin does and keep brain cells alive.

'While we are focussing on stroke, neuroprotective drugs may also be of interest in other conditions that see early death of brain cells including Alzheimer's and motor neurone disease,' he suggests.