Motor Neurone Disease: New Insight about how it works

When we imagine how research results can change society or help us make new bounds in medical science we think of proving a hypothesis or cracking a code, but sometimes research that refutes a theory can be just as beneficial, as scientists can eliminate a hypothesis from the mix and save years of wasted-time investigating dead ends and a team of German researchers has just done exactly that.

Writing in the journal Proceedings of the National Academy of Sciences (PNAS), the team refute a widely accepted hypothesis about a causative step in neuro-degenerative conditions.

These results deal specifically with animal models of human amyotrophic lateral sclerosis (ALS), more commonly known as Motor Neurone Disease, but the findings also have implications for other neuro-degenerative diseases such as Alzheimer's or Huntington's disease.

One of the ways neuro-degenerative diseases manifest themselves is in the loss of axons - essentially, the transmission lines for electrical signals in individual nerve cells - and synapses, the key sites for communication between them.

In the past, such damage has been attributed to deficits in the bi-directional transport of organelles, such as the intracellular power plants called mitochondria, along the axons of nerve cells.

The team, from the Technische Universitaet Muenchen (TUM) and Ludwig-Maximilians-Universitaet Muenchen (LMU), put these previously-held assumptions to the test in one of the most thorough tests carried out to date.

They used novel imaging techniques, with high resolution in both space and time, to observe changes in both axon morphology and organelle transport in several different animal models of ALS.

Their results show that transport deficits and axon degeneration can develop independently of each other, throwing into question the theory that one is a direct cause of the other.

They observed axonal organelle transport in living tissue in real time, and in a way that enabled them to track the movement of individual mitochondria, using a novel imaging approach that involves transgenic labelling.

They were also able to observe transport of another kind of organelle, endosome-derived vesicles. Several different animal models of ALS were investigated, all of which are based on human mutations associated with the disease.

One of the study authors, Professor Thomas Misgeld from the Institute of Neuroscience at the Technische Universitaet Muenchen, comments on their findings: 'We do think these insights have implications for other studies of ALS, or even studies of other neuro-degenerative diseases.

What our experiments really say is that it is not easy to develop faithful models of neuro-degenerative diseases.

So it might be worth spending more effort to get better animal models, as this is the only way forward for mechanistic studies, while always checking them against human pathology or human-derived cellular models.

In the meantime, it is probably prudent to work with several of the available models in parallel. Moreover, in more general biological terms, our results also speak to the relationship between axonal transport disruptions and degeneration - which might not be as tight as we assumed. Here we have a lot more to understand.'

The iPSoALS project brings together researchers from France, Germany, Israel and Sweden with the aim of better understanding ALS disease mechanisms.

For more information, please visit: Technische Universitaet Muenchen (TUM)

Reversing age-associated effects in MS patients

New research highlights the possibility of reversing ageing in the central nervous system for multiple sclerosis (MS) patients.

The study is published today, 06 January, in the journal Cell Stem Cell.

As we get older, our bodies' ability to regenerate decreases. This is not only true for our skin (which is evident in the wrinkles that develop as we age) but also true for other tissues in the body, including the regenerative processes in the brain.

For diseases which often span several decades and are affected by regenerative processes, such as multiple sclerosis, this can have massive implications.

In multiple sclerosis, the insulating layers that protect nerve fibres in the brain, known as myelin sheaths, become damaged.

The loss of myelin in the brain prevents nerve fibres from sending signals properly and will eventually lead to the loss of the nerve fibre itself.

However, early in the disease, a regenerative process, or remyelination, occurs and the myelin sheaths are restored. Unfortunately, as people with MS age, remyelination decreases significantly, resulting in more nerve fibres being permanently lost.

However, a new study in mice shows that the age-associated decline in the regeneration of the nerve's myelin sheath, or remyelination, is reversible.

The proof of principle study demonstrates that when old mice are exposed to the inflammatory cells (called monocytes) from young mice, the ageing remyelination process can be reversed.

Professor Robin Franklin, Director of the MS Society's Cambridge Centre for Myelin Repair at the University of Cambridge, said: "What we have shown in our study, carried out in collaboration with Dr Amy Wagers and colleagues at Harvard University, is that the age-associated decline in remyelination is reversible.

We found that remyelination in old adult mice can be made to work as efficiently as it does in young adult mice.

"For individuals with MS, this means that in theory regenerative therapies will work throughout the duration of the disease.

Specifically, it means that remyelination therapies do not need to be based on stem cell transplantation since the stem cells already present in the brain and spinal cord can be made to regenerate myelin - regardless of the patient's age."

MS affects approximately 100,000 people in the United Kingdom, 400,000 in the United States and several million worldwide. Symptoms of the disease can include the loss of physical skills, sensation, vision, bladder control, and intellectual abilities.


More information: The paper 'Rejuvenation of regeneration in the aging central nervous system' will be published in the 06 January edition of Cell Stem Cell.

Multiple sclerosis starts in brain’s outer layers

Researchers at the Mayo Clinic and Cleveland Clinic have reversed the traditional understanding of how multiple sclerosis (MS) begins and travels in the brain.

The common view is that the disease starts in the centre of the brain, in the white matter mostly found there, and then moves toward the outer layers, such as the cortex.

But this study, which is unique because it focused on the brain tissues of patients in the very early stages of MS, shows the opposite: that it moves from the outside in.

It begins in the “subarachnoid space,” which surrounds the brain, cushions it and is filled with cerebrospinal fluid. From there it moves into the white matter. This animation shows how the two hypotheses differ.

The findings are also significant because they support the hypothesis that inflammation, not neurodegeneration, is a main driver of the disease.

The authors conclude that it is “overwhelmingly likely” that MS is fundamentally an inflammatory disease, and not a neurodegenerative disease similar to Alzheimer’s.

Researchers are not entirely sure exactly causes MS, but the prevailing theory is that it is an autoimmune disease in which the body’s own immune system attacks and destroys its own myelin, a fatty substance essential to the nervous system. It protects the crucial nerve fibres enable different sections of the brain to communicate.

When myelin is damaged (as in MS), messages between the brain and the body are delayed or blocked, leading to MS symptoms such as blindness, numbness, paralysis, and thinking and memory difficulties.

“Our study shows the cortex is involved early in MS and may even be the initial target of disease,” co-lead author of the study and Mayo Clinic neurologist Dr. Claudia F. Lucchinetti stated.

“Inflammation in the cortex must be considered when investigating the causes and progression of MS”, she says. She and her co-author, Dr. Richard Ransohoff of the Cleveland Clinic, published the results of their study in the New England Journal of Medicine.

Study offers hope of 'repairing' MS damage

Scientists have identified a way of prompting nerve system repair in multiple sclerosis (MS).

Studies on rats by Cambridge and Edinburgh University researchers identified how to help stem cells in the brain regenerate myelin sheath, needed to protect nerve fibres.

MS charities said the "exciting" Nature Neuroscience work offered hope of restoring physical functions.
But they cautioned it would be some years before treatments were developed.

MS is caused by a defect in the body's immune system, which turns in on itself, and attacks the fatty myelin sheath. It is thought to affect around 100,000 people in the UK.

Around 85% have the relapsing/remitting form of the condition, in which "flare-ups" which cause disability, are followed by a recovery of a level of the lost physical function. In this form of MS, there does appear to be some natural myelin repair.

However, around 10% of people are diagnosed with a progressive form of MS, where the decline continues without any periods of remission.

In addition, people with the relapsing/remitting form do often go on to develop what is called secondary progressive MS, which affects them in the same way.

Early days yet
However, much more work is needed - both to test if the mechanism works in people with MS and to see what drugs might be needed to promote the effect.

Professor Charles ffrench-Constant, of the University of Edinburgh's MS Society Centre for MS Research, said: "The aim of our research is to slow the progression of MS with the eventual aim of stopping and reversing it.

"This discovery is very exciting as it could potentially pave the way to find drugs that could help repair damage caused to the important layers that protect nerve cells in the brain."

More information at BBC News - Study offers hope of 'repairing' MS damage

Breakthrough, nerve connections are regenerated after spinal cord injury

Researchers for the first time have induced robust regeneration of nerve connections that control voluntary movement after spinal cord injury, showing the potential for new therapeutic approaches to paralysis and other motor function impairments.

In a study on rodents, the UC Irvine, UC San Diego and Harvard University team achieved this breakthrough by turning back the developmental clock in a molecular pathway critical for the growth of corticospinal tract nerve connections.

They did this by deleting an enzyme called PTEN (a phosphatase and tensin homolog), which controls a molecular pathway called mTOR that is a key regulator of cell growth. PTEN activity is low early during development, allowing cell proliferation. PTEN then turns on when growth is completed, inhibiting mTOR and precluding any ability to regenerate.

Trying to find a way to restore early-developmental-stage cell growth in injured tissue, Zhigang He, a senior neurology researcher at Children’s Hospital Boston and Harvard Medical School, first showed in a 2008 study that blocking PTEN in mice enabled the regeneration of connections from the eye to the brain after optic nerve damage.

He then partnered with Oswald Steward of UCI and Binhai Zheng of UCSD to see if the same approach could promote nerve regeneration in injured spinal cord sites. Results of their study appear online in Nature Neuroscience.

“Until now, such robust nerve regeneration has been impossible in the spinal cord,” said Steward, anatomy & neurobiology professor and director of the Reeve-Irvine Research Center at UCI. “Paralysis and loss of function from spinal cord injury has been considered untreatable, but our discovery points the way toward a potential therapy to induce regeneration of nerve connections following spinal cord injury in people.”