Promising news for keeping the motor neurone neighbourhood safe

There was standing room only in the first of the dedicated scientific sessions of the Symposium last week. All had gathered to hear Prof Stan Appel inform them of the latest chapter of this story on the role of inflammation in MND.

Listening to his presentation I got the gist of the overall positive message – a real step forward in MND research – but to report in any more detail of how and why was a step too far for my brain when I was in Sydney! Reading through my notes when I got back to the office, I was determined to get to the bottom of this science. It helped me to write a non-technical summary of it as I went. It’s perhaps a bit more technical than our normal blog posts – but I couldn’t resist the opportunity to (try and) share my new found knowledge. So here goes:

Inflammation is one response of the immune system. The immune system is a community of cells that exist within your body to protect it from damage and to maintain its status quo. Given its important function, it is perhaps reassuring to know that how it works is mind-blowingly complex!

In the brain and spinal cord, a slightly different defence system exists in comparison to the rest of the body. It is now common knowledge that motor neurones are surrounded by cells that support their function – known as glial cells. Within the community of these glial cells there are ‘police’ cells called microglia. Prof Appel’s lab has contributed many elegant studies to a consensus of research showing that in MND these police cells operate a delicate balance between protecting the environment around motor neurones and triggering a toxic atmosphere. Gradually the toxic atmosphere prevails.

In Sydney, Prof Appel discussed another component of this defence system, ‘regulator T-cells’. Continuing the police analogy, T-cells patrol the blood, rather than the brain and spinal cord tissue of microglia. As their name suggests, regulator T cells regulate the response rate of removing toxins and maintaining a healthy environment, in particular they regulate microglia by sending out specific chemical signals.

Prof Appel wanted to know how the interaction of T-cells with microglia is affected in MND. He found that a large ‘police presence’ (or high numbers) of regulator T-cells influence microglia to maintain their protection of motor neurones. In other words, large numbers of regulator T-cells kept motor neurone death at low level, showing itself as a slower phase of disease progression. As the levels of regulator T-cells get lower, the microglia turn toxic and the rate of progression of the disease speeds up. These conclusions were based on studies in mice models of MND and in patients at different stages of MND – by analysing blood samples for the presence of regulator T-cells and comparing this with what they knew of their symptoms.

This information presents two opportunities to MND researchers – firstly if therapies can be developed to maintain the levels of these regulator T-cells they may slow down the disease; and in the meantime, chemical markers in the blood, used in these studies, may be a valuable biomarker to measure the rate of progression.

Round up of news from the 22nd International Symposium on ALS/MND

Word cloud of symposium reporting 2011
Word cloud from our symposium reporting in 2011, creating on

We organise the International Symposium on ALS/MND every year, and it is regarded as the premier medical conference on MND and a highlight of the research calendar.  In 2011, the symposium was held in Sydney Australia where 650 researchers, clinicians and healthcare professionals  from 33 countries met to discuss recent advances in MND research and care from around the world.

To give you a taste for what the symposium is all about, and tell you what the findings that were being discussed really meant, we wrote over 8,000 words in our daily articles on this blog.

Here’s a brief guide along with links for the full articles:

Rip roaring start to the symposium
Being welcomed by Glen Doyle on behalf of the Gadigal tribe of Australia was a stunning start to the symposium. This was followed by a spectacular explanation using ping pong balls and rat traps to explain how all forms of MND need a trigger.

Copying, transporting and creating proteins – what could possibly go wrong?
TDP-43, a protein which can cause MND, is normally involved in editing or reading up to one third of all proteins within the cell – now that’s a city fat cat type of job!

Mediating the delicate balance between protection and damage
The speed of progression in MND appears to be dictated by the delicate balance between protection and damage of the ‘innate’ immune cells in the nervous system. Could tilting the balance back to protection be a good therapeutic strategy?

If you were a car, would you be a Ferrari or a Focus?
People with MND may well come from among the Ferrari’s of the human race…

A quick peruse of the posters
An update on the Neuralstem stem cell clinical trial and answering whether riluzole has an effect on a drug that is currently being trialled called dexpramipexole.

Next chapter of BMAA detective story
A tale that has been woven for the past 60 years including an exotic island, bat eating natives, and how researchers are striving to work together to solve this mystery.

Beauty and the beast – when misfolded proteins cause havoc
Tale as old as time… find out how and why proteins can become disfigured into ‘beasts’ to cause MND.

The season of the gene
Researchers are beginning to look to genetics in a new way. It seems that there is a huge potential to make discoveries and connections a lot faster.

Windows to the brain
Brain scanning technology reveals that people with MND have different levels of brain activity than those without the disease. This study demonstrates another step forward toward a clinical test for MND.

Clinical trials low down, down under
Recent clinical trial findings were discussed including the Dutch lithium trial, memantine trial, Nogo-A (GSK) trial and biomarker findings from the first phase of the NP001 trial.

Changing fashions of MND models
Stem cells are not the panacea of models, they’re an arrow in a quiver of techniques…

The 23rd International Symposium on ALS/MND will be held in Chicago, USA on 5-7 December 2012.

Final thoughts from Sydney

Attending a three day scientific meeting is quite an intense experience, my brain has been working hard and by this morning, there were leaks of stress all over the place!

So in some ways it was quite a relief to walk into the final session of the meeting this afternoon, but in other ways quite sad too. Dr Bryan Traynor from the National Institute for Health in the USA gave a concise, accessible and comprehensive overview of the ground breaking discovery of the C9orf72. It was good to hear the detective story of how he and his colleagues came to actually make the discovery, the analogy of gradually narrowing down the area of DNA to look in from a city the size of Sydney, to a long street to eventually to a small one-road-through-not-very-googable village was much appreciated. (It also manage to increase the species of analogy animals mentioned at the meeting to cows – not one that I’d heard mentioned until then).

For me however, the highlight of this session was Prof Kevin Talbot’s concluding presentation on ‘Where to from here’. It was an articulate summary of what the whole MND research community has been told, discussed and digested over the three day conference and suggested some pointers of where we should go next.

That’s me done until I get back to home!

My grateful thanks to Kelly and Kate back in the office for all their preparatory work for these posts, it was a team effort.

Read our official press release from day three of the symposium.

Changing fashions of MND models

Models of MND are important both to understand the causes of MND and to quickly, efficiently and accurately screen and develop new treatments for it.

A number of key developments both in terms of technological know-how and new understanding of genetics of MND have led to the development of new models discussed at on the last day of the symposium.

Stem cells
The session was opened with a presentation on what is arguably the most glittering and exciting of these new models, that of using so called ‘iPS’ cells. The principle behind iPS cells (induced pluripotent stem cells to give them their full name), is that it’s possible to take a skin cell from someone with MND, coax it back into basic stem-cell-like state and then change it into motor neurones. The idea that this was even possible was scientific heresy say five years ago. The beauty of this technique is that you then have living human motor neurones in dish in the laboratory.

Dr Kevin Eggan from Harvard University Massachusetts USA is one of the leading lights in this technology and he treated us to an update of his latest research. “In itself, ALS is an interesting test tube for stem cell research” he said, adding “this is my first ALS meeting, I’ve enjoyed it and learnt a lot”. Aswell as being the first time that it was possible to study the cells directly affected in MND (motor neurones), iPS techniques also allow researchers to study the behaviour of motor neurones at as close to the actual disease conditions as possible.

Are they really motor neurones?
In the first part of this talk Dr Eggan explained and demonstrated that the cells that he and his colleagues have grown really are motor neurone-like and that they do behave like motor neurones. However he did caution that this model is not the panacea of ALS models, it’s an arrow in a quiver of techniques.

How do these motor neurones behave?
The second half of his talk concentrated on whether these human motor neurone models behave differently to motor neurones grown from skin cells of unaffected people.

When given the same growing conditions, motor neurones derived from people with SOD1 mistakes (mutations) were found to be less plentiful when growing ‘in a dish’ than those derived from healthy individuals. The SOD1 motor neurones also display a different pattern of electrical activity (transmitting electrical activity, is, after all, one of the main functions of motor neurones). The next steps of this research will be to double check that the effects seen in cells with SOD1 mutations really are due to this faulty gene and investigate the effects of other known genetic causes of MND in these cells.

Of mice and men
Moving from a new model to an old and arguably less fashionable one, Dr Greg Cox was given the title of “Are mice a good model for human ALS”. His first slide was to turn this question on its head and state that humans are a terrible model for mouse ALS! His point was that there are so many things that are unknown in human MND that generating a truly accurate mouse model for it was an almost impossible task. Saying this, he went on to discuss three key essentials for any mouse model, so called face, construct and predictive validity. Towards the end of his presentation he shared some results of one of this own studies, explaining that there is an area of our genetic code, not identified in MND before, that seems to carry a mistake that causes symptoms of MND.

Read our press release from day three of the symposium.

Clinical trial low down, down under

“After a time where patients and sponsors of trials alike had become disheartened about the lack of positive clinical trials, it is exciting to see so many positives, including the recently approved Neudexta, and the dexpramipexole study”, commented Professor Robert Miller from the Forbes Norris ALS/MDA centre in San Francisco opening the discussions on clinical trials.

Designing a good trial
As MND is a rare disease clinical trials are notoriously difficult to design in order to ensure that they have meaningful results. Designing better and quicker clinical trials will aid us to find the answers as to whether a treatment is beneficial or not, without losing the significance of a study. It is therefore important that clinical trial designers share their methods with one another. In the first presentation of this session Prof Miller gave us some pointers on how this may be done, looking at every aspect from designing shorter trials with fewer participants, to how an effect is measured.

The next few talks were then dedicated to discussing results from recent clinical trials:

Prof Leonard van den Berg, from University of Utrecht, The Netherlands presented the results from the Netherlands lithium clinical trial. Unfortunately, although they found the treatment to be safe, no beneficial effects were seen. The results from the UK clinical trial of Lithium Carbonate, which was designed in a different way with more participants will be published early 2012.

Dr Ming Chan from University of Alberta, Canada discussed the results of the recent memantine pilot trial for MND. This trial treatment was administered via tablets. Twenty four people took part in this study and were randomly divided into one of three groups who would receive either: high dose memantine; low dose memantine; or a placebo (dummy) drug. Overall, the trial results suggested that the treatment is safe, and at the higher dose a larger, multi-centre clinical trial for memantine may be warranted.

Nogo-A (GSK1223249)
Dr Pierre-Francois Pradat from the Centre for MND in Paris, France presented the very hot-off-the-press results of the Nogo A trial – a drug developed by the pharmaceutical company GlaxoSmithKline, that is delivered directly into the blood stream via an intravenous (IV) drip. This was a Phase I ‘first in man’ study, given to people with MND first. This is different to other Phase I clinical trials, as healthy volunteers are more commonly used for this stage of trial.

The aim of this study was to ensure that the treatment was safe and well tolerated in people with MND. Dr Pradat discussed that the drug was found to enter the body effectively. The investigators saw trends (ie they are not statistically sure) of benefits in slower decline of respiratory function, of a scale that measures the functional capabilities of people with MND called the ALS-functional rating scale (ALSFRS) and muscle strength. Tentative plans are underway for a larger clinical trial next year.

NP001 is a drug developed by Neuraltus Pharmaceuticals.  This trial treatment is administered directly into the bloodstream via an intravenous (IV) drip.

At present a Phase II clinical trial for NP001 is underway in the USA and we acknowledge that a lot of people living with MND are interested in hearing more about the status of this trial. This talk however, focused on the Phase I trial to tell us the effects of NP001 on potential markers of disease progression in MND (known as biomarkers), identified through the earlier Phase I trial. We can therefore not comment on the current status of the Phase II trial in this blog article.

As discussed by Prof Miller, from Forbes Norris ALS/MDA Research Center in San Francisco USA and principle investigator to the trial, it is thought that NP001 may be beneficial as the levels of proteins which are increased as a result of an inflammation response in MND are decreased by the drug. They also concluded that the levels of these inflammatory response proteins can be related to the rate of progression for people with MND and could potentially be used as a marker.

Read our official press release from day three of the symposium.

Windows to the brain

With the huge advances in biology, it can seem that areas such as brain scanning are relatively stagnant, but we are starting to see a growing momentum in the field, allowing researchers to learn more about the ‘real time’ events occurring in individuals with MND.

Hand in hand with the improving technology that allows us to visualise the structures and connections inside people’s brains, as the scanners get more powerful, are the new ideas and techniques that researchers are applying. These help them to get the most from their studies by pooling their data and analysing it in different ways.

Giving the plenary presentation on this neuroimaging session, titled ‘The Past, Present and Future of Neuroimaging in MND’ was Dr Martin Turner, one of our Medical Research Council/ MND Association Lady Edith Wolfson Clinical Research Fellows, who heads the groundbreaking Biomarkers in Oxford project (BioMOx).

Dr Turner described the potential uses of the three main imaging technologies: PET (positron emission tomography) MRS (magnetic resonance spectroscopy) and, in particular, MRI (magnetic resonance imaging) which have developed considerably over the past decade, giving a ‘world tour’ of the results from the leading centres in MND neuroimaging. Indeed, he spent so much time highlighting the work of others that he only briefly mentioned his own very recent and exciting research from the BioMOx study, where he has used advanced imaging techniques to compare how the brains of people with MND are physically linked up (called structural connectivity) with how the brain actually works (called functional connectivity) as compared to unaffected ‘controls’. Having just read his latest findings on the flight over, I think they deserve a slightly fuller mention.

Second results published from BioMOx project
In the study, 25 people with ALS, the most common form of MND, took part in this part of the study, as well as 15 healthy individuals.

As the motor neurones in the brain degenerate, he saw an increase in functional connectivity and activity in other parts of the brain, associated indirectly with movement. This ‘boundary shift’ described by Dr Turner has an extended pattern of activity beyond standard motor systems.

Not surprisingly, the brain has a great capacity to compensate and adapt to damage (recovery from stroke being a prominent example). However, Dr Turner’s study also shared that people with slower progressing forms of MND had much lower levels of increased connectivity than those progressing rapidly, which was more than controls. This wasn’t simply due to people with a slow progression being at an earlier stage of the disease, as those with a slow progression at relatively advanced steps of MND were also included.

He speculates that the increased functional connectivity might actually be an active contributor to disease progression. One possibility is that in recruiting additional brain areas, together with some possible ‘rewiring’ occurring, it is altering with the complex balance of ’excitation and inhibition’ – in other words the way other neurons in the brain send positive or negative signals that control how active the motor neurons are.

This study demonstrates yet another step forward towards the development of robust clinical test for MND to speed up the diagnosis process. Although there is a lot of work to done to confirm these findings, we’re definitely heading in the right direction.

OK – back to the meeting!
Dr Turner highlighted one of the major challenges – namely the question of whether we can apply these techniques to clinical trials (as has been done in multiple sclerosis and which has revolutionised the search for treatments). However, several problems need to be overcome, not least the fact that patients taking part in a trial may be very different in their disease presentation and/or at different stages of the disease. So there is still a lot of noise in the system, which is why Phase III clinical trials often need to involve several hundred patients. Performing multiple MRI scans on each participant would add huge cost to any study.

Dr Turner also highlighted the challenge, but also a tremendous opportunity, to perform ‘comparative MRI’, linking the events going on in mouse models of the disease with those in man. Dr Robyn Wallace, from University of Queensland, elaborated on this theme with her presentation of imaging data from the SOD1 mouse. Using an intensely powerful scanner (10 times more powerful than a standard hospital scanner) she could show evidence of degeneration of the motor nerve tracts in the mouse spinal cord and was able to see these changes from around symptom onset. This is the first study to show that this form of MRI can show changes in the same mouse as the disease progresses. She also performed very detailed MRI studies on the intact spinal cord removed from mice – examination of the spinal column on its own improves the resolution and also allowed her to immediately perform the detailed histological examination of the tissue changes that had occurred. It is hoped that this very detailed work will help in the interpretation of human MRI scans in the future.

Finding out when MND begins
How early can we measure changes in man? Since 1997, Dr Mike Benatar from Emory University, has been performing studies on individuals who carry the SOD1 gene mistake (mutation) but have not yet shown any symptoms of MND, in an attempt to answer the question of when the neurodegenerative process begins, as opposed to when the first symptoms appear. Certainly, research from other fields, such as Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, indicates that the process can start years before.

Dr Benatar reported his findings using both MRI and MRS. To date, he has not been able to show any major ‘structural’ differences (nerve cells that are physically connected in the brain) in his ‘pre-inherited ALS (the most common form of MND)’ individuals compared to healthy individuals of the same age, but he is seeing some metabolic changes using MRS, which can measure the relative signals of a small number of different chemicals in the spinal cord. He is continuing with the study, but extending the range of inherited forms of the disease to include inherited cases of ALS patients and ‘pre-inherited ALS’ volunteers carrying TDP-43, FUS, VCP and C9ORF72 genetic causes.

For those of you who might ask how MRI scans work, here’s a very brief explanation:
Magnetic resonance imaging (MRI) is based on the concept that some molecules in the brain, in particular water molecules, will line up in a particular direction in a strong magnetic field. If a brief pulse of radio waves is then applied from a different direction, it causes the molecules to change direction briefly and then ‘wobble’ as they realign themselves back to the magnetic field.

The amount of wobble and the time taken for the molecules to return to a rest are like a fingerprint. Using computer analysis, MRI can pick up changes in brain structure, connectivity and even brain activity.

Read our official press release on day two of the symposium.

The season of the gene

“Welcome to this afternoon’s genetics session, which I hope will convey elements of hope and excitement about the season of the gene” were Professor Teepu Siddique’s (from Northwestern University, USA) opening remarks on a series of talks that really did live up to this standard. To me each talk was like being read chapters of a thriller novel, each was gripping with its own story to tell, but by the end of the session I was really buoyed up with hope, enthusiasm and an appetite for more!

Prof Siddique’s research lab have contributed two important new discoveries in MND genetics in the last few months alone (UBQLN2 and SQSTM1), so he was very well placed to begin with an overview of how recent discoveries allow us to make sense of much of what has been to date.

Prof Siddique started his talk by discussing what we can tell about MND by looking at human motor neurones down a microscope . Using some very elegant studies of the build up and removal of proteins tagged with different colour labels he demonstrated that many causes of MND (ie genetic mistakes in TDP-43, SOD1 and FUS genes, and the randomly occuring sporadic form) all have a build up of ubiquilin2. The next part of the story was to explain what this protein was doing there – what sequence of events or malfunctions in the motor neurone has caused the protein to be there. Time and again he demonstrated that at the heart of disease-causing damage in MND is the protein recycling system (see Prof Mayer’s post a month or so ago). This was summed up for delegates by playing a TV commercial of blindfolded women trying to identify different parts of an animal (a rhino this time) and only when their blindfolds were removed was the whole story revealed.

The phrase an ‘elephant in the room’ is used in reference to the presence of a huge topic that no-one is talking about. But the huge topic in genetics was most definitely getting an airing this afternoon – that of the discovery of the C9orf72 gene defect. Speakers either talked about it in light of the way that it links together a number of diseases where there is evidence of frontotemporal dementia as well as signs of motor neurone damage. Or the fact that the actual gene defect seen in C9orf72 is so different to older genetic discoveries in MND – in so much that the damage is caused by lots of extra letters included in the instruction, rather than a ‘spelling mistake’ in the instruction by removing, substituting or deleting individual letters. Now that genetic researchers are tuned in to looking to genetics in a new way and looking for changes in new places, it seems that there is a huge potential to make discoveries and connections that much faster. Personally I can’t wait to read the next instalment.

Read our official press release from day two of the symposium.

Beauty and the Beast – when misfolded proteins cause havoc

Beauty is often said to be skin deep, but in terms of proteins, their appearance means everything. Its appearance and shape denotes its role in our cells and allows it to attach itself to other proteins and parts of the cell to perform its role. If its appearance is significantly altered through misfolding, turning it into a ‘beast’, it can no longer perform its role properly, rendering it useless. Not only does this mean that a protein’s regular role is not being performed, but it also means that there could be a build up of beastly, misfolded proteins in the cell, if they are not recycled efficiently. Misfolded proteins was the topic of discussion at one of this afternoon’s sessions of the symposium – topics ranged from the machinery or location involved in the folding to which proteins, SOD1 and TDP-43 among them, are being misfolded and why.

Protein Origami

When our proteins are first built in our cells, they can be related to a piece of paper. On its own, it can’t perform its regular function so it needs to be folded into its final form – in this example, a paper aeroplane. To do this, it is fed inside a network of connecting tube like structures called the endoplasmic reticulum – or ER for short, where it is folded and sent to its final destination to perform its role within the cell.

This everyday process within the ER can become stressed when misfolded proteins build up inside which triggers a response to try to restore order. Our cells cannot maintain this for a long period, which isn’t normally a problem as ‘regular’ issues are short-lived. However, when proteins are regularly misfolded in diseases such as MND, this can cause pandemonium as the response that normally restores order cannot cope with the sheer volume of misfolded proteins, which causes the motor neurones to degenerate.

Stressful response to MND

In the first presentation of this session, Dr Julie Atkin from La Trobe University, Australia discussed how there is increasing evidence to suggest that ER stress is linked to MND. Although ER is found in every cell in our body, little is understood about it in neurones. In a previous study, her laboratory demonstrated that ER is actively trying to restore order, both in the spinal cords of mice that model the disease and people with MND. This response is one of the first MND causing events to occur in a mouse model. Dr Atkin’s current area of study is centred on understanding how this response is activated in MND. In her overview she demonstrated that many of the damaged proteins recently associated with MND cause ER stress.

Their most recent studies have suggested that issues with transport away from the ER could cause the build up of misfolded proteins leading to stress and a response to restore order. Understanding how the ER stress response is activated could be important in order to device new treatments that target this system, stop the neurone from being stressed, and potentially stop it from dying.

The next few talks moved to looking at how and why some of these proteins may become unfolded and how this is helped by the cells’ coping and balance-maintaining systems. 

The beginning of Nic Dokholyan’s talk really made me sit up and take notice, no cell pathway diagrams (cartoons), no images or cells fluorescing different colours under a laser microscope and no ‘blots’. It was a cartoon of an elephant, representing the Chinese proverb of a blind man and an elephant.

 He explained that this represented his impression of the knowledge of the MND research community, after attending the International Symposium on ALS/MND in Berlin two years ago. Everyone knew their own particular part of the elephant (or the underlying cause of MND) really well, but no-one had put all the bits together to get the overall shape / see the whole cause of MND. Doing a rough assessment of all of the known causes of MND (via a method he described but I didn’t quite catch or understand –probably the latter!), he concluded that SOD1 misfolding should be at the centre of the ‘elephant’. Results showing that copies of SOD1 protein are modified in blood samples from people who do not have MND (including a sample of his own) was the starting point for the research he presented in Sydney. Dr Dokholyan’s went on to describe a series of elegant techniques demonstrating how a very minor, small alteration to the surface of a protein can affect its ability to misfold and accumulate within motor neurones. (Perhaps going back to the earlier beauty analogy, this is the equivalent of having a mole or facial blemish removed.)

Read our official press release from day two of the symposium.

Next chapter of BMAA detective story

On Thursday morning, Profs Paul Cox and Walter Bradley chaired a session titled ‘Beyond Guam: New Aspects of the BMAA Hypothesis’. This was the latest chapter in a detective story, involving botanists, epidemiologists, clinicians and biochemists that goes back 60 years….

Back in the early 1950s, American doctors started documenting a high incidence of a strange form of MND in the native Chamorro Indian population of the Pacific island of Guam. Those affected exhibited a mix of symptoms covering motor neuron degeneration, dementia and Parkinson’s disease – giving rise to the official name Amyotrophic Lateral Sclerosis-Parkinson-Dementia Complex, or ALS-PDC for short.

Early epidemiology studies linked the disease to a likely environmental exposure with a long-term incubation period, possibly a slow-acting toxin of some type. Subsequent studies linked the disease with the seeds of a member of the cycad family. Cycad seeds formed part of the islanders’ diet and these seeds contain a variety of different chemicals, including some that are toxic to nerve cells. One of these, beta-N-methylamino-L- alanine (BMAA) was a prime suspect.

But cycad seeds don’t make BMAA themselves – it is actually made by a form of cyanobacteria (blue-green algae) that live in the roots of the cycad plants. The BMAA toxin is then concentrated in the plant seeds, which were ground up as flour to make a form of bread.

In the lab, it could be shown that BMAA readily killed nerve cells, did so at concentrations that were much higher than those that would be found in the cycad bread. This led the epidemiologists to ask the question ‘What else eats cycad seeds?’ The answer was flying foxes – a type of fruit eating bat – and flying foxes in turn are considered a delicacy by the locals…

As Prof Cox explained in his introductory overview to the delegates, we have a very nice example of biomagnification. BMAA is made by algae, is concentrated in cycad seeds, is further concentrated in the bats and is finally eaten by the locals, where it presumably builds up in brain tissue over time.

This theory isn’t universally supported by researchers – for example, if a genetic factor was involved, it would likely be more prevalent in an isolated, island population such as Guam. However, the epidemiologists like to point out that the bat population has plummeted over the past 40 years (perhaps due to increased use of guns by the islanders or the introduction of an invasive tree-climbing snake) as has the incidence of ALS-PDC!

Of course, cyanobacteria are found all over the world, so it begs the question of whether BMAA might be present in very low levels in other places, perhaps acting as a subtle factor that predisposes people across the world to develop MND? Certainly, BMAA has been found to be present in water sources in various locations, in particular marine environments where, as explained by Dr Estelle Masseret (University of Montpellier) it can be further concentrated in shellfish. It has also been shown to be present in the brains of people with neurodegenerative diseases who have never been within a thousand miles of Guam.

Cyanobacteria - Dr Paul Cox

The levels of ‘free’ BMAA in the brain are relatively low, so a theory has emerged in recent years that most of the BMAA in the brain tissue is ‘protein-bound’ – not sticking randomly to proteins, but actually being unwittingly incorporated into the protein structure during the manufacturing process. This isn’t surprising, since BMAA is an amino acid and amino acids are the building blocks of every protein in our body.

The difference with BMAA is that it is an ‘unnatural’ amino acid. By this I mean that proteins are normally made from a combination of 20 amino acids. BMAA isn’t one of them, so when it gets incorporated, it can subtly alter the structure of the protein. And when protein structure is altered in neurons, it invariably leads to the aggregation of proteins, one of the classic pathological hallmarks of neurodegenerative diseases. Since our neurons have to last a lifetime, an accumulation of BMAA and misfolded proteins over many years could make neurons more susceptible to damage.

One big unanswered question is which amino acids is BMAA being mistaken for? Through some elegant experiments, Prof Ken Rogers (University of Technology, Sydney) showed  that part of the protein making ‘machinery’ is specifically mistaking BMAA for serine, the amino acid that is structurally the most similar. The ‘machinery’ is question is an enzyme called tRNA synthetase and Prof Rogers pointed out that if this process is inhibited in mice, the neurons are the first to start to show damage, indicating that they are particularly vulnerable if tRNA synthetase is not doing its job correctly.

It does raise the question of whether BMAA is incorporated more into proteins that contain the largest proportion of serine amino acids. That question has not yet been addressed, but it is interesting that the protein TDP-43, which is known to misfunction in up to 90% of cases of MND, is a protein that is made up of an unusually high number of serine amino acids,

As with many aspects of biomedical research, this session raised more questions than answers, but the really encouraging fact was that the questions were coming from scientists outside the immediate BMAA field. It will take additional expertise to definitively demonstrate whether or not BMAA is indeed a common risk factor that might prime people to develop neurodegenerative disease later in life. This session, together with a follow-up workshop organised for the end of the day, will throw up the key next steps in this field of investigation – how to strengthen the evidence in cell and animal models, how to improve the analytical methods and how to collaborate more closely together in the future, drawing in new expertise from across the world of neuroscience.

Read our official press release on day two of the symposium.

If you were a car, would you be a Ferrari or a Focus?

People at increased risk of MND might be the human equivalent of high performance cars – built for speed and agility but becoming unreliable once they reach a high mileage.

There is much anecdotal evidence amongst MND clinicians and those affected by the disease that people who develop MND tend to have been relatively physically fit before their diagnosis, often having been involved in various athletic pursuits throughout their life. This prompted MND Association-funded researcher Dr Martin Turner to ask the intriguing question: Is an athletic physique an outward sign of a subtle predisposition to MND? But how could he make a sensible measurement of ‘athletic physique’ in order to answer such a question? Or as he put it in his presentation on Thursday morning, do people with MND have motor system run to death, or is it a motor system born to run?

A pragmatic way of looking at this was to look at the history of coronary heart disease and whether this is linked to a likelihood of developing MND later in life. Dr Turner has recently published this study in the Journal of Neurology, Neurosurgery and Psychiatry). Through very careful examination of hospital medical records, he and his colleagues compared numbers of MND cases in over a hundred thousand people with a history of coronary heart disease to an even larger group with no known heart problems.

The study did reveal a slightly increased occurrence of MND in the group with healthy hearts, providing indirect evidence that MND is more likely to occur in people with greater levels of ‘fitness’. Dr Turner’s results were in fact corroborated by the findings of another more general study of lifestyle and environmental factors presented in the same session. Dr Marc Huisman’s meticulously executed and much admired questionnaire-based study of the Dutch population also suggested that people with MND were less likely to have relatives with heart disease, indicating a more genetically robust cardiovascular system, amongst many other findings.

Dr Turner’s findings are intriguing but there is still plenty more work to do and many questions are left unanswered. There are other studies that support the possibility of an increased MND risk in people with a healthy cardiovascular system and lean build but of course these two characteristics are also a result of undertaking higher levels of exercise – the question of whether exercise itself contributes to MND still won’t go away. However, Dr Turner’s work supports the concept that if you’re born with a natural leaning towards athletic prowess, you may excel at sport (or in evolutionary terms, hunting down your dinner) but your nervous system wiring may also be more vulnerable to MND as you age – a factor that’s only become problematic with the dramatic increases in life expectancy that have come about in the last couple of hundred years.

As Dr Turner put it at one our spring conferences this year, people with MND may well come from amongst the Ferraris of the human race. With clearer identification of risk factors, prevention of MND becomes a more realistic possibility. It may be that in future the Ferraris can undertake a specialised servicing schedule to ensure they have a greater chance of breaking the 100,000 mile barrier with their electrics in good working order!

Read our official press release on day two of the symposium.