MND stem cell study identifies TDP-43 astrocytes as not toxic to motor neurones

Funded by the MND Association, international researchers have used stem cell technology to learn more about the relationship between motor neurones and their support cells.

These findings highlight the potential of stem cell technology as a tool to create new human ‘in a dish’ cellular models of disease to learn more about the causes of MND.

Prof Siddharthan Chandran and Sir Prof Ian Wilmut at University of Edinburgh looking at a stem cell image

The research group included MND Association funded researchers Prof Siddharthan Chandran and Sir Prof Ian Wilmut from University of Edinburgh, Prof Chris Shaw from King’s College London and Prof Tom Maniatis from Columbia University in America.

This important finding was published in the scientific journal PNAS on 11 February 2013. This new finding follows on from previous work published by this research group in 2012 where they demonstrated the proof of principle of creating human motor neurones with MND in a dish.

Why we need an astrocyte model of MND

Astrocytes, so called because of their star-like appearance, normally act as neurone support cells to nourish and protect motor neurones. They act with motor neurones to ensure that they can continue to function.

From previous studies, we know that when these cells begin to dysfunction, they can become toxic to motor neurones to contribute to MND. Finding out why astrocytes can cause motor neurones to degenerate is an issue of ongoing debate – we recently gave an update on this from the International Symposium.

Being able to grow human astrocytes in a laboratory dish is of importance to be able to learn more about the relationship between astrocytes and motor neurones in MND.

Creating human astrocytes in a dish

Using cutting-edge stem cell technology, the research group reprogrammed skin cells into astrocytes in a laboratory dish. The skin cells were donated by people with MND who have a family history of the disease caused by known mistakes in a gene called TDP-43.

Led by Prof Chandran and colleagues, the research group aimed to identify whether these cells would develop the ‘hallmarks’ of MND in a laboratory dish.

By studying the characteristics of these human astrocytes with faults in the TDP-43 gene, the research group identified that they shared the same qualities as cells affected by MND. The astrocytes had increased levels of TDP-43 found in areas where it isn’t usually found – outside of the control centre of the cell. They also found that the astrocytes didn’t survive as long as astrocytes created from skin cells of people that didn’t have MND.

This means that the human astrocytes created by Prof Chandran and colleagues using stem cell technology develop MND-like characteristics. This new model can be used to study how motor neurones develop the disease in a system that is directly relevant to people living with MND.

Answering whether faulty astrocytes affect healthy motor neurones

The next question that this research group wanted to answer was whether these faulty astrocytes had an effect on healthy motor neurones.

By growing faulty TDP-43 astrocytes with healthy motor neurones, the research group identified that the survival of motor neurones was not adversely affected.

This was surprising as other research groups have shown that when astrocytes have faults in the SOD1 gene (which cause one in five cases of MND with a family history) that motor neurones are compromised, even if the motor neurones were originally healthy.

TDP-43 is found within tangled lumps in over 90% of cases of MND (irrespective of whether it was caused by an inherited genetic mistake). However, when MND is caused by SOD1, TDP-43 is not found in these tangled lumps. This important difference could be leading to the key difference in whether astrocytes become toxic to contribute to causing MND.

These findings will of course need to be verified by an independent research group to determine that they are valid, but the results suggests that SOD1 and TDP-43 could be causing havoc in motor neurones in slightly different ways, both avenues leading to MND.

Our Director of Research Development, Dr Brian Dickie comments: “From a therapeutic perspective this is important because it means that specific treatments targeted at astrocytes may only be relevant and effective, in specific subsets of patients who will have to be carefully selected for drug trials.”


Our news release on this finding.

March 2012 finding: Association-funded stem cell study achieves milestone

Serio A et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. PNAS 2013

Structure of C9ORF72 repeat identified by MND Association funded researchers

New exciting findings announced today provide the first insight into the structure and function of a repeated six letter genetic sequence in an MND gene called C9ORF72.

Understanding the function of C9ORF72, and how it could go wrong to cause MND, could assist researchers in the future to identify potential treatments that target the disease.

The finding was identified by University College London researchers including Dr Adrian Isaacs and Dr Pietro Fratta. Dr Fratta is a recipient of a Medical Research Council/MND Associaiton’s Lady Edith Wolfson Clinical Research Fellowship.

Their findings were published in the reputable scientific journal Scientific Reports on 21 December 2012.

C9ORF72 – the plot thickens

In 2011, MND Association funded researchers discovered that a repeated six-letter code within a gene called C9ORF72 can cause MND and a related condition called fronto-temporal dementia (FTD) for approximately 40% of cases with a family history of MND and/or FTD. Having a family history of MND is rare and affects 5-10% of people with MND.

In people without MND, this six-letter code (GGGGCC) is repeated up to 30 times. In C9ORF72 MND or FTD, this sequence can be excessively repeated between 700 and 1,400 times.

Since this pivotal discovery, researchers have started their journey to search for answers to find out more about C9ORF72 and how it can cause MND.

This study aimed to identify whether the six-letter code normally forms a specific structure when in its copy (RNA) form. Forming a structure normally means that something has a particular role. If this seemingly innocent piece of repetitive code does form a structure, then it could mean that excessively repeating it could cause problems by being over active, or by stopping other functions.

Dr Adrian Isaacs
Dr Adrian Isaacs

Dr Isaacs who led the study explains, Nothing is currently known about how the mistake in C9ORF72 kills motor neurones. The mistake in C9ORF72 is similar to mistakes that cause some other neurological diseases.”

“In these diseases the mistake leads to the formation of toxic aggregates of RNA –RNA is a copy of DNA that is made when a gene is switched on and is important for the generation of proteins.”

 Dr Issacs and colleagues used advanced analytical chemistry to identify the structure that the repeated six-letter code (GGGGCC) forms and to suggest its potential role.

RNA G-Quadruplex, glorified Battenberg cake

This shape, and structure that has been identified for the repeated six letter code in the copy of C9ORF72 is called an ‘RNA G-quadruplex’.

In real life terms, an RNA G-quadruplex would look –with some artistic license granted – like a Battenberg cake.

RNA G-quadruplex looks like a Battenberg cake

The four coloured sponge squares would be the individual letters of the code – all being the ‘GGGG’ part of the sequence running along the length of the structure and forming four ‘slices’.

Each line of four Gs (coloured length of sponge), is stuck together to another line of four Gs in the structure by strong hydrogen bonds (the jam!).  This forms the four-square pattern that makes up each ‘slice’. Each line of four Gs is also attached to its phosphate backbone, which is the outermost section of the structure (the marzipan).

The only addition to the Battenberg that’s missing to create an RNA G-quadruplex would be a metal ball, or ion sitting in the middle of each of the four slices.

What does it do?

Having a structure means that the repeated six-letter code is of importance to find out whether it has a function. Having a function would then mean that the genetic expansion could have a detrimental effect on its usual role in the cell.

The forming of these Battenberg cake-like structures means that it could perform a specific role in the body. To date, quadruplexes have been identified as having a number of roles in the body, including editing copies of genes to create functional proteins.

Dr Pietro Fratta
Dr Pietro Fratta

Dr Pietro Fratta explains how this structure could play a role in C9ORF72 MND, “One possibility is that the RNA G-quadruplexes accumulate in motor neurones and then different proteins within the cell somehow bind to this structure and get stuck. As a result the motor neurones malfunction and perhaps even ultimately die.”

Commenting on these findings, MND Association’s Director of Research Development Dr Brian Dickie said “The UCL scientists have opened up an exciting new avenue of research.”

“At the moment we know very little about whether, or how, these RNA structures may be linked to MND, but evidence from other diseases indicates that they are biologically active and therefore likely to be important to the function and health of nerve cells.”

Following this finding, the next steps for researchers will be to determine the function of the G-quadruplex in nerve cells, and the effects of the excessive repeat in MND has on the function of these quadruplexes.

Paper reference: Fratta P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Scientific Reports 2012 DOI: 10.1038/srep01016

Read our news release on this story.

Of yeast and men: reducing toxic effects of TDP-43 as a potential treatment for MND

A collaborative American research group, led by Prof Aaron Gitler from Stanford University School of Medicine in California, has identified a potential therapeutic target for MND using yeast.

The toxic activity of the MND-linked protein TDP-43 was suppressed when a gene called DBR1 was deleted from yeast and mammal cells.

The study marks the first steps in the identification of a treatment that can target TDP-43, which is found to clump together in over 90% of cases of MND.

The study was published in the prestigious journal Nature Genetics.

Toxic tangle of TDP-43

To develop effective treatments for MND, we need to find ways of targeting the systems that go wrong to cause the disease.

One hallmark of MND is the accumulation of tangled lumps of protein – including TDP-43.

For years, researchers didn’t know whether the clumps of TDP-43 they could see was a by-product of MND, or a cause of the disease. That was of course, until researchers identified that mistakes in the TDP-43 gene can cause inherited MND in 2008. Since then, researchers have been busy creating new disease models to learn more about how TDP-43 can cause MND.

So far, at least 400 studies have been published to better understand TDP-43 in MND (search terms ALS, FTD, variations of TDP-43 on Pubmed).

Yet we still don’t know whether TDP-43 is doing harm by being over active or under active. We do however know that it’s found in the ‘factory floor’ of the cell, called the cytoplasm, when it’s normally found in the control centre. Using this information, it’s possible to focus on therapies that decrease the toxic effect of TDP-43 rather than to increase or decrease the amount of TDP-43.

This is exactly what a collaborative American research group, led by Prof Aaron Gitler has done.

Using yeast, Prof Gitler and colleagues performed two unbiased genetic screens in different laboratories using different techniques. By doing this, they verified a list of genes that can modify the effects of TDP-43 when deleted – by either enhancing the toxic effect or suppressing it.

Out of the list of resulting modifiers, the research group chose to investigate a suppressor of TDP-43 toxicity, a gene called DBR1.


Far from a classic Aston Martin sports racing car (also named DBR1), DBR1 in biological terms is an ‘RNA lariat de-branching enzyme’. It plays an important role in recycling genetic ‘junk’.

Our genes are split into segments within our genetic code, separated by what’s often referred to as ‘junk’ DNA. These sections of junk, known as introns, don’t code for anything, but often perform other important roles.

When a gene is copied into its intermediate form of RNA (before these instructions are used to create a functional protein), it needs to be edited to remove the introns, leaving the vital instructions intact. This involves the introns forming loops of RNA – called lariats – which cut away from the rest of the copy. This leaves only the instructions for the gene product. These lariats then move away from the control centre of the cell (the nucleus) to be recycled.

DBR1’s role normally cuts these lariats open into strings, which can then be recycled. When in a lariat form, RNA is resilient to being recycled. DBR1 therefore plays an important role in recycling intronic RNA in the cell.

What happens when DBR1 is deleted?

When the research group deleted DBR1, intronic lariats accumulated in the factory floor of the cell (the cytoplasm). These lariats then competed to bind to TDP-43, acting as a decoy. This stopped TDP-43 from performing its dastardly deeds when faulty – chopping up essential RNAs within the cell –which could be contributing to the cause of MND.

By deleting DBR1 in yeast and in rat neurones grown in a dish, the research group identified that it increased the chance of neurone survival by nearly 20%.

This means that identifying a therapy that can decrease the amount of DBR1 could be a potential treatment for MND.


Prof Gitler and colleagues independently verified their results from the genetic screen in yeast using different laboratories and different methods.

This is significant in terms of its reliability, as this often has huge repercussions for future research.

This topic was recently discussed in the popular science magazine New Scientist in an article called ‘Is medical science built on shaky foundations?’ In the article, the writer explains that a number of pharmaceutical companies have recently announced their failure to replicate a large number of promising results of potential drug targets from published studies.

It’s vital that if we are to identify a treatment for MND that works, that the evidence that led it to be tested in humans is solid. Gaining evidence to suggest the effectiveness of a treatment means replicating the results using independent researchers and using different methods to put an idea through its paces. This ensures that the original results aren’t identified as a coincidence and can be relied upon.

The decision by Prof Aaron Gitler’s group to reproduce their genetic screen independently, using different methods should be applauded. It means their findings are unlikely to be added to the heap of potential targets that cannot be reproduced in other studies.

Being thorough to identify potential targets may take more time, but it’s likely to produce more fruitful results in the long haul.

Looking forward

There are many steps left to climb with the development of a treatment that targets TDP-43. For example, the research group will need to determine whether stopping DBR1 could itself be toxic due to side effects. They also need to determine where the ‘therapeutic window’ is with this therapy – where it’s both effective and safe.

This study also identified many other modifying factors for TDP-43, which can begin to be investigated by other research groups for their potential as a therapy for MND.

As this is the beginning of the story of TDP-43 specific treatments for MND, it will inevitably be a long journey to answer these questions and to bring treatments to the doctor’s prescription pad.

Hopefully, the beacon of rigor and scientific righteousness that this study symbolises will continue and we will see the first TDP-43 therapy being developed for MND in the coming years.


Maria Armakola et al Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genetics 2012; doi:10.1038/ng.2434

Encouraging NP001 clinical trial results for MND

Promising results from a Phase II clinical trial for a drug called NP001 have been announced by the biopharmaceutical company Neuraltus.

The trial, conducted in America, suggested that NP001 is safe, well tolerated and could be beneficial for MND.

Following these encouraging results, Neuraltus plan to begin a larger, Phase III trial of NP001 in the second half of 2013. As the Phase III trial is still being planned, we do not have details on American recruitment centres, nor what the eligibility criteria will be.

The trial
The Phase II clinical trial for NP001 was rigorously controlled. This means that it was randomised, double-blinded and placebo controlled. These are important factors in controlling possible bias. We have more information on why these factors are important on our website.

The trial included 136 people living with MND in America across multiple centres.

Participants were randomised into three groups to receive an intravenous infusion of either high dose NP001, low dose NP001 or placebo (inactive substance) treatment for six months. They were then followed for an additional six months. Approximately 45 people were used in each treatment arm.

The results
Results suggest that the treatment was safe and well tolerated. Promising signs of effectiveness were also identified, but were not statistically significant to draw firm conclusions as to whether the treatment could be effective for MND.

The trial organisers state in their press release that 27% of people taking the high-dose NP001 did not progress during the trial period. It’s important to treat these results with a certain degree of caution, as approximately 10% of people taking the inactive placebo also did not progress during the same period as measured by changes in the functional rating scale.

The results provide enough evidence to warrant a larger scale trial to investigate this treatment further.

This finding also importantly identifies the optimum dose that should be used in this larger-scale clinical trial, as their results suggest that a higher dose could be more likely to yield a beneficial effect than the lower dose.

Finding out the optimal dose is an important part of Phase II clinical trials to ‘fine tune’ the details to provide the treatment with the best chances of demonstrating its success at Phase III.

Importance of sharing results via peer-review
These results will need to be published in a peer-reviewed scientific journal. Peer review is an important process to determine whether findings are valid and that appropriate standards have been used in the study. Once published, these findings will also be used by the scientific community to add to their knowledge.

Importance of Phase III planned for 2013
The promising results identified in Phase II will need to be confirmed in the Phase III trial planned for the second half of 2013.

Leading UK clinical trial researcher, Prof Nigel Leigh said, “A larger Phase III randomised placebo-controlled trial is required before we can be confident that these positive trends are consistent and clinically significant.”

Dr Brian Dickie, the MND Association’s Director of Research continues, “We welcome Neuraltus’ plan to initiate a Phase III trial to determine whether NP001 is beneficial for people living with MND.”

Discussing results at the International Symposium on ALS/MND
Results from the Phase II NP001 trial will be discussed in more detail at the 23rd International Symposium on ALS/MND, to be held on 5-7 December 2012.

The symposium, organised by the MND Association provides a platform for researchers, clinicians and healthcare professionals to discuss the latest developments in research and care, including discussing results from recent clinical drug trials.

We will be reporting live from the symposium via our research blog. To ensure you have daily updates from the symposium, please sign up to our automatic email alerts on the right hand side of the blog.

Our news release
Neuraltus’ press release
International Symposium on ALS/MND
Brian’s NP001 blog article

New fellowship explores how C9ORF72 causes MND

Dr Johnathan Cooper-Knock
Dr Johnathan Cooper-Knock, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Dr Johnathan Cooper-Knock from the Sheffield Institute for Translational Neuroscience (SITraN) has been awarded with the fifth Medical Research Council (MRC)/MND Association Lady Edith Wolfson Clinical Research Fellowship.

Through his three-year fellowship, Dr Cooper-Knock will use the MND Association’s DNA bank to study how recently discovered mistakes (known as mutations) in a gene called C9ORF72 can cause the disease.

Dr Johnathan Cooper Knock explains, “I believe that the genetics of MND are a key to understanding both the cause of the disease and how to treat it. The discovery of mutations in C9ORF72 are a great opportunity to get a hold on mechanisms of disease which has so far been elusive. I am excited by the opportunity my fellowship will give me to pursue this important discovery.

“By the end of my fellowship I aim to have contributed significantly to the understanding of disease mechanisms related to C9ORF72 dysfunction in MND. As a result I hope to have identified a number of therapeutic targets for development into new treatments by myself and others.”

C9ORF72: the facts so far

We know that a repeated six-letter code within a gene called C9ORF72 can cause MND and a related condition called fronto-temporal dementia (FTD) for approximately 40% of cases with a positive family history of MND and/or FTD.

Most genetic mistakes found in MND to date have been swaps of genetic letters, which can change the meaning of that part of the gene. The C9ORF72 genetic mistake on the other hand, is a repeat expansion. This means that six letters within the genetic code (CCCCGG) are repeated hundreds of times for people with C9ORF72 MND. In healthy individuals, this repeat is found about 30 times. We already know that the exact size of the repeat varies substantially between people with this genetic mistake. How this repeat causes MND and how the size of the repeat may affect disease progression is currently unknown but this is something that Dr Cooper-Knock wants to find out.

We also don’t know what role C9ORF72 normally has in the body. Even its name, which stands for ‘chromosome 9 open reading frame 72’ refers to where it is in the genetic code and not what it does. This isn’t unusual as it’s currently estimated that we have over 20,000 genes, and understandably, researchers haven’t yet found out what every one of these does – including C9ORF72.

So far, 96 journal articles have been published about C9ORF72 (by searching on Pubmed for C9ORF72). The oldest of these was published in 2011, and describes the original MND/FTD C9ORF72 finding. All subsequent articles on C9ORF72 have been of a direct consequence from this pivotal genetic discovery in the past year.

These 96 studies were focused on finding out how many people have the C9ORF72 genetic repeat and finding out what this mistake ‘looks like’ both clinically in terms of progression rates, age of onset and symptoms; and in terms of post-mortem findings to compare with other forms of MND. Coincidently, the most recent post-mortem and clinical C9ORF72 finding was authored by Dr Cooper-Knock (when searching for C9ORF72 and post mortem on PubMed).

It’s reassuring to know that researchers aren’t resting on their laurels with this genetic finding. There’s a huge international research effort in place to push forward our understanding of C9ORF72, with a number of our own newly funded projects, starting later this year, dedicated to creating new laboratory models of this genetic mistake to better understand how it can cause the disease.

How do we currently think C9ORF72 causes MND?

Due to the sheer size of the repeat expansion in C9ORF72, it’s thought that it causes MND by disruption of the editing process of genetic information.

I’ll explain: In real life terms, our DNA can be thought of as being held within a library, which is the control centre of the cell (the nucleus). Each book (gene) is stored on a particular shelf (chromosome). Gene ‘books’ aren’t allowed to be taken out of the nucleus, but they can be photocopied. These copies (RNA) are edited and transported out of the nucleus to be used as instructions to create proteins that perform specific roles in and sometimes out of the cell.

Unlike real life books, genes are fraught with errors, variations and nonsense from one person to the next. It looks messy, but it’s normal. Genetic editors are needed to edit and chop the RNA into a readable format so that it can be understood by the parts of the cell that use RNA as instructions.

As normal, healthy copies of C9ORF72 hold approximately 30 repeats to be chopped out as RNA, the effect of having much larger repeats may be having a knock-on effect on the efficiency of the editing process. This could then lead to a much higher risk of developing MND.

Finding out exactly how C9ORF72 can cause MND, and whether this theory is right, will provide us with a deeper insight into MND and potentially provide therapeutic targets that can be further investigated.

Dr Cooper-Knock’s fellowship

Dr Cooper-Knock will be using a cutting-edge genetic technique called ‘gene expression profiling’ to study the various levels of RNA in samples provided by people with the C9ORF72 genetic mistake. From this, he’ll find out which genes are switched on and off because of the C9ORF72 repeat expansion.

He will also study whether the size of the C9ORF72 repeat expansion has an effect on symptoms or progression rates to identify factors that may modify disease progression and may therefore be targets for future therapies.

Technology specialised for identifying misassembled RNA will also be applied to skin cells donated by people with the C9ORF72 repeat expansion who have MND/FTD and healthy controls. This will help to elucidate what the C9ORF72 protein does.

As well as skin cells from people with MND/FTD, this study will use post-mortem brain and spinal cord tissue from people with the C9ORF72 repeat expansion and healthy controls within the Sheffield tissue bank; as well as cells from the blood of C9ORF72 patients and healthy controls obtained from the MND Association’s DNA Bank.

Talking about the importance of people with MND having provided these numerous samples Dr Cooper-Knock said “Without the participation of patients and their families MND research will get nowhere; and equally with their participation, doors are opened towards new and exciting treatments. At this time, with discoveries like the mutations in C9ORF72 to build from, we can do even more with the participation of those who have been affected by this disease, who like us are passionate to see it cured.”

More information:
Read our official news release on our MND Association website.
Find out more about our DNA bank.

EPHA4 gene influences survival in MND

An international research group spanning seven countries and including 23 researchers has identified a gene that modifies survival in MND. The gene, called EPHA4 was identified through a zebrafish genetic screening project and verified in rodents and humans with MND. The study was led by Prof Wim Robberecht, who has previously been funded by the MND Association and who is the Chair of our International Symposium on ALS/MND. The findings were published in the prestigious journal Nature Medicine this week.

What did the research group find?

By screening zebrafish for genetic factors that can modify the progression of MND, the research group identified EPHA4. By stopping, or slowing down the activity of EPHA4, they identified that MND zebrafish can be rescued and rodents (mice and rats) can live longer.

They also identified that MND vulnerable motor neurones have a higher level of EPHA4 than those at a lesser risk of developing the disease. This also means that a low level of EPHA4 confers to a lower risk of MND.

The research group then looked to humans to see if anybody with MND had mistakes in the EPHA4 gene that resulted in a change in survival. The group found two people with MND with genetic differences in the EPHA4 gene. These two people lived with MND for an exceptionally long time. As these genetic differences result in a lower level of EPHA4, this suggests that EPHA4 could be a valid therapeutic target for MND.

What does EPHA4 do?

Ephrin type-A receptor 4 (EPHA4 for short), plays a vital role in the development of our nervous system, in maintaining the shape of the neurone and in preventing regeneration after injury.

As our motor neurones grow, the projecting length of the neurone (the axon) needs to be guided to grow toward the right areas to connect to its respective muscle. To do this, a complex ephrin negative signalling system is used to guide the growing neurone in the right direction.

In real life terms, this signalling pathway can be thought of as somebody blindfolded, navigating a traffic cone maze. This person (the neurone) doesn’t want to move into an area cornered off by traffic cones (the corresponding ephrin signal). As the neurone can’t see where it’s going, it feels its way around using Eph receptors like EPHA4. The neurone moves away from ephrin signals as it ‘feels’ them. This eventually leads to the neurone reaching its target destination (the muscle).

To physically make the neurone move, when an ephrin signal connects to the ephrin receptor, the inner workings of the neurone are called into action. To find out more information on this, please read our previous article about Profilin1, which was found to be a cause of MND last month.

As EPHA4 plays an integral role in stopping neurone growth, it isn’t surprising that it also plays a role in stopping regeneration of neurones after injury. For example, in mice that have spinal cord injury (this was a study unrelated to MND), by genetically stopping the EPHA4 signal, new axon growth can be seen. With mice that have spinal cord injury that have a normal level of EPHA4 signal, growth cannot be seen.

The above non-MND study, along with the current EPHA4 finding further suggests that a lower level of EPHA4 can result in a longer survival because of its inability to perform its usual function to its usual extent. This incompetance seemingly allows the protection of neurones from degenerating at it’s normal pace.

As an additional note, you may be thinking that it seems counterintuitive that humans have additional signals that stop processes like regeneration when less complex animals like frogs still have this ability. Unfortunately, it’s a bi-product of mammalian evolution that continues to baffle scientists!

What does this mean for people with MND?

This finding unfortunately does not mean that a new genetic test will become available for EPHA4.

This discovery does however, offer another target for research institutes to look into and develop therapies that could slow down disease progression by lowering the amount of EPHA4.

Although this research is likely to take years to develop toward a clinical trial* in humans, it’s promising to see yet another exciting genetic advance that could have an impact on finding a better treatment for MND in the future.

*It’s important to point out that therapeutically lowering the EPHA4 signal in humans would not necessarily mean that neurones could regenerate as seen in the zebrafish. Many different signals other than EPHA4 prevent a human motor neurone from regenerating and from finding its target muscle. However, finding a way to lower the EPHA4 signal may still slow down progression, as seen in mice in this study.

What does this mean for the future of MND research?

Further studies are needed to verify and expand on these exciting results.

This finding means that researchers can explore this pathway in more detail as it, in conjunction with the recent Profilin 1 finding, suggests that this guidance/growth system of motor neurones may play an important role in the development of MND.

Van Hoecke et al. Nature Medicine 2012 doi:10.1038/nm.2901

Munro et al. PLoS One 2012 10.1371/journal.pone.0037635

Our blog article on Profilin1

Profilin 1 identified as a cause of inherited MND

An MND causing gene called profilin 1 has been identified as the cause of about two percent of cases of inherited MND. This finding provides new insights into the causes of MND and suggests a potential role of the cellular scaffolding in MND. The finding was published in the 15 July edition of the prestigious journal Nature. This international collaborative study was led by Dr John Landers, at the University of Massachusetts Medical School, USA.

Using cutting-edge genetic technology, Dr Landers and colleagues first identified genetic mistakes in the profilin 1 gene in two families with inherited MND. To verify these findings, they went on to identify five additional families that also have mistakes in the profilin 1 gene. They did this by examining the genetic spelling of this gene in 272 further people with inherited MND (with no known genetic cause). This means that the genetic mistake could account for approximately two percent of cases of inherited MND.

Four different genetic mistakes were identified in the profilin 1 gene in the seven identified MND families. Three of these genetic mistakes were not found in any healthy controls, which mean that these mistakes are most likely a direct cause of MND. The forth genetic mistake was identified in a small number of healthy control samples, which could mean that this mistake could be a less significant cause of MND.

What does profilin do?

Profilin plays a vital role in maintaining and shaping the cells scaffolding – the cytoskeleton.

The cytoskeleton can be thought of as being made up of stacks of Lego bricks, called filaments. To maintain the shape of the cell, these bricks push against the cell membrane. To stretch and move the cell, more bricks (called actin) are added to the outermost end of the filament, which forces the membrane to extend. Toward the innermost end of the filament, the actin units separate, similar to pulling off individual bricks from the bottom of a stack, where they’re then collected and attached to profilin. Profilin then recharges and recycles the actin units, so that they’re ready to be added to the top of the filament again.

What did the research group find?

Through this study, the research group identified that the ability of profilin to attach to actin is affected by the genetic mistakes, making it ‘clumsy’. They also identified that the mistakes affect the ability of the cells to grow, which could be an attributing factor to how these mistakes can cause MND.

In this study, the researchers also confirmed that profilin is normally found throughout the ‘factory floor’ of the cell, the cytoplasm. However, when profilin is faulty the research group identified that it often assembles into clumps of protein marked for destruction – a hallmark of MND.

Interestingly, they also identified that when profilin is faulty, TDP-43 also clumps together. This suggests that faulty profilin may also cause MND through its effect on TDP-43. It’s also worth noting that when TDP-43 is faulty, profilin is not found within the clumps of faulty TDP-43 suggesting that profilin has an effect on TDP-43 and not vice-versa.

What does this mean for people with MND?

Profilin 1 is the twelfth MND causing gene to be identified in MND, which means that we are one step closer to knowing all of the genetic causes of MND. Learning more about how genetic mistakes can cause the rare inherited form of MND (5-10% of cases)  helps us to learn more about all forms of MND as the more common sporadic form is clinically indistinguishable to the inherited form.

As this genetic mistake is thought to only be attributed to a small number of families with MND, it is currently unknown if a genetic test will be developed for inherited MND. If you have inherited MND and want to find out more information about genetic testing, please speak with your doctor or neurologist.

What does this mean for the future of MND research?

These findings will need to be verified in larger numbers in different populations to determine a more accurate figure for how many families are affected by mistakes in the profilin 1 gene. More work will also need to be done to determine how the cytoskeleton is affected in MND and whether it can provide any therapeutic targets to treat MND in the future.

In summary, problems with the cytoskeleton have long been thought to be involved with MND, but having a direct genetic cause of MND strongly associated with the cytoskeleton will most likely reignite this avenue of research in the coming years.

Wu C-H et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 2012 doi:10.1038/nature11280

The social and educational effects of caring for a parent with MND

Olly Clabburn

Last year, we helped Olly Clabburn to advertise an opportunity to take part in his dissertation research project on our website and in our monthly membership magazine Thumb Print. 

To give you some feedback on what drove him to study the social and educational effects of caring for a parent with MND and his key findings, he’s written us a guest blog:

When I was seven years old my Dad was diagnosed with Motor Neurone Disease. At the time, I found it hard to understand why he had to stop doing the normal ‘Daddy things’. He stopped going to work, began speaking in a slow and strange way, and then had to give up his car which was extremely hard for him.

Gradually over the three years in which we looked after him at home, myself and my family became full-time carers for him. This involved helping him when he fell over, getting him drinks, food, toileting amongst a plethora of other things. Yet my friends at primary school seemed to be having a very different life at home while I was doing a variety of things for my Dad which I believed to be ‘normal’.

As my Dad began to deteriorate more, caring at home became more and more challenging. Consequently, he moved into the Hospice for the final few years where he could get the specialised help that was now required. Although the Hospice staff were amazing for my Dad and family, the inevitable happened in April 2004 when he passed away after a long battle with MND.

Years passed and after studying Psychology at Sixth-form, I developed a keen interest to how we work as people and why we ‘do’ certain things. I then enrolled in Lancaster University to study Psychology in Education for which I conducted a dissertation research project. Fuelled by my experiences, I decided to further investigate young-carers and their experiences caring for a parent with MND. My project subsequently was titled ‘the social and educational effects of caring for a parent with Motor Neurone Disease’.

Upon deciding to research this specific area, I knew recruiting participants would be challenging with MND being so rare and not generally considered to impact upon young-people’s lives. I therefore established communications with the MND Association in the hope for some advice or guidance. Ultimately, the association made my research possible as without their assistance, I simply would have not been raise awareness of my study and conduct the research.

The MND Association allowed me to publish a letter in the Summer 2011 edition of Thumbprint outlining my study and need for young people who were once young carers. The Association later added a webpage under the research section of the Association’s website which also assisted with recruitment. As a result of the magazine and webpage, I managed to recruit and interview 7 participants who had once, or currently were, caring for a parent with MND.

Upon writing up my research, there were 6 clear themes raised by the participants which were considered to be the main social and educational effects of caring for a parent with MND.

1)      DIAGNOSIS: Many of the young carers felt somewhat confused and unaware about MND and what their parent being diagnosed actually meant. Consequently, it often came as quite a surprise when a parent’s care needs increased. It was also found that the terminal nature of MND was often hidden from the young-people in an attempt to shelter them.

2)      YOUNG CARER DUTIES: One of the key duties a young person adopted after the diagnosis, was increased responsibility for household chores enabling their healthy parent to spend more time with the MND patient. It was also noted that the young people tended to adopt a more ‘social care’ role, meaning they would often sit with their parent and keep them company rather doing the more intimate caring tasks.

3)      RESPONSIBILITIES:  Older siblings tended to adopt a more parental role for younger siblings by helping out with school runs, help with homework or carrying out more caring tasks for the ill parent to shelter their younger sibling. It was also noted that all participants had a greater appreciation for their healthy parent and a closer relationship as a result of MND.

4)      EDUCATION: All participants emphasised the importance of education (school/college/university) providing a period of escapism. This meant that for the time in which they were in the educational setting, they could temporarily forget about life at home and be ‘normal’. Interestingly,  it was also noted that having a parent with MND brought some educational benefits. For example, their parent being permanently at home provided an opportunity to help with homework. It was also commonly acknowledged that the disease/bereavement fuelled a great deal of motivation for the young person to achieve educational success.

5)      SOCIAL: It was noted that peers and friends provided another extremely important method of escapism. Participants found that they could gain advice or simply ease the burden by discussing life at home. It was additionally noted that peers may introduce the young carer to new hobbies and interests which also allowed the individual to escape or channel emotions. However, it was also outlined that guilt was also a common feeling when with peers and not at home with their parent.

6)      POSITIVE ASPECTS: Overall the participants in the research outlined a variety of positive aspects that they have drawn from the experience. Most notably, a feeling of maturity compared to peers, the ability to accurately empathise with others, closer relationship with family members and increased motivation leading to educational success.

Finally, it was noted that a diagnosis of MND is inevitably traumatic and creates many negative outcomes for all involved. The research however aimed to reinforce the idea of optimism thus coinciding with the ‘MND Month for Optimism’ campaign.

Young carers will spend much of their time caring for their terminally ill parent and later suffer bereavement. Nevertheless, the research highlighted the positive benefits that individuals can gain from this known negative experience.

Irish angiogenin research leads to promising results

Angiogenin was discovered as a cause of MND for a small number of families affected by the inherited form of MND in 2006. Since then, research has been ongoing to better understand the role of angiogenin and to see if we can use this information to develop future treatments.

This week, we learnt of two inter-woven news stories related to angiogenin. One was related to a new biological finding of the vital role that angiogenin plays and the second expands on this work and led to the testing of angiogenin in mice that model MND. Prof Jochen Prehn leads the Irish research group who made these findings from Royal College of Surgeons in Ireland.

Angiogenin to the rescue!

Through their research, the Irish group identified that angiogenin acts as an emergency service call from our motor neurones to support cells. The findings were published in the Journal of Neuroscience and help us to better understand both the biology of angiogenin and how we can use this to develop future treatments for MND.

In essence, the research group outlined the following pathway for how angiogenin works and how it can go wrong:

When motor neurones are in trouble, they send out angiogenin as their ‘999’ call. This ‘call’ is received by our support cells – the neighbouring astrocytes (so called because they are star shaped).

As angiogenin whizzes it’s way between the outside of the motor neurone and the astrocyte, it needs to find a particular ‘door’ to enter. Cells are quite particular as to what they let inside, so no ‘Joe Bloggs’ can simply walk into a cell unless it has permission to pass (the exception being if it’s something really small!).

As angiogenin plays an emergency service role, it has a pass to be led into the astrocyte. Through this study, the research group were able to specify exactly which ‘gatekeepers’ and doors are used by angiogenin to enter the astrocyte.

Once inside the astrocyte, angiogenin goes into the control centre of the cell – the nucleus. Here, it rolls up its sleeves and starts editing copies of (supposedly, emergency service) genes to help the astrocyte to create more supportive proteins. We don’t yet know what these genes are, but it was declared as a next step for the project in the published paper.

In MND cells with mistakes in the angiogenin gene, it’s function as an editor of gene copies doesn’t happen. Angiogenin is still created in the motor neurone, and passes through into the astrocyte, but it’s supportive function isn’t happening.

This study therefore raises the possibility that angiogenin could be developed and tested further as a possible future treatment for MND to help this supportive function continue.

Testing angiogenin in mice

The second angiogenin story relates to a presentation that was given at the recent European Network for the Cure of ALS (ENCALS) meeting in Dublin by Prof Prehn’s group.

As a follow on to their previous work, Prof Prehn’s research group tested the effectiveness of angiogenin as a treatment for MND in mice. These are called pre-clinical studies, and are essential to provide enough evidence to move to human clinical trials.

In a similar move to our Cogane study, the group have identified through a rigorous MND mouse study that angiogenin could be a promising treatment. Overall, they concluded that it prolongs life by 10 days in mice (which is more effective than riluzole), increased the survival rates of motor neurones, and delayed the progression of symptoms when given after symptom onset.

This study will need to be published and verified in another model, or by another lab following preclinical guidelines to ensure that these results are reliable. After that, the next steps would be for human clinical trials to be initiated. This means that angiogenin could start to be tested in humans in the next few years.

In summary…

Together, these studies prove the value in better understanding the causes of MND, even when the genetic mistake may only cause the disease for a small number of families.

Being able to move a biological finding from the laboratory toward the clinic is always encouraging news.

All in all, it’s great news for the first day of our month of optimism!

MND Association funded researcher Dr Martin Turner wins ENCALS Young Investigator Award

We’re pleased to announce that Dr Martin Turner has been awarded with the European Network for the Cure of ALS (ENCALS) Young Investigators Award 2012.

Dr Martin Turner
Dr Martin Turner, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Dr Turner was awarded with the MRC/ MND Association Lady Edith Wolfson Clinical Research Fellowship in 2008 for his study to identify biomarkers in MND (called BioMOx). Since then, Dr Turner has already published two findings from his five-year disease marker study in the prestigious journals Neurology and Brain. Using advanced brain scanning technology, his study has identified a common pattern of nerve damage in the brains of MND patients. This holds the promise of a much-needed disease marker.

Talking about why he thinks the ENCALS award is so important, Dr Turner said:

“The ENCALS award marks a major highlight in my career.”

“I am passionate about MND, and feel privileged to help care for those living with the most challenging of diseases. To be recognised as having made a useful contribution to research as well, by international leaders in the field, means an enormous amount.

“It is 13 years since I began as a PhD student under Professor Nigel Leigh, whose ground-breaking ideas about brain changes in MND first sparked my interest. I was fortunate to meet Professor Kevin Talbot in 2003, and through his support and partnership I have been able to develop these ideas alongside leading brain imaging neuroscientists at Oxford University.

“I have never felt more sure that progress is accelerating in MND research, and I am pleased to be adding something to the wider global effort.”

Funding promising researchers

One of our research aims, is to develop the research workforce. Dr Turner talks more about how our funding has helped to develop his career:

“The Lady Edith Wolfson Clinical Research Fellowship scheme, uniquely linked to the Government-funded Medical Research Council through the MND Association, has been critical to my development as an MND researcher.

“These highly competitive 5-year Fellowships don’t simply provide the funding for the experimental studies, but crucially allow me to devote most of my time as a consultant neurologist solely to the care and research of MND patients. There is no simple way to specialise like this within the standard NHS framework, and such schemes are a vital way to help develop a strong UK academic neurology workforce in MND.”

Commenting on this story, our Director of Research Development, Dr Brian Dickie said “We’re delighted that one of our Lady Edith Wolfson Fellows has won this prestigious international award. The Fellowships were created to attract and retain the brightest and the best young clinicians to MND research and it is a fitting tribute to the knowledge, expertise and dedication that Dr Turner brings to this important field of MND research.”

More information:

Our official news release

Go to the BioMOx website to find out more about this project

Find out more about ENCALS

Our research aims

BioMOx findings: