Zebrafish study provides innovative ideas for new treatment strategies

A study on zebrafish has increased our understanding of how motor neurones work and has provided potential clues for the development of future treatments for MND. The study, led by Dr Catherina Becker from University of Edinburgh, showed that a unique motor neurone repair system found in zebrafish can be enhanced if a particular signal called Notch1 is stopped. The results were published in the 29 February edition of Journal of Neuroscience.

What did they find?

Unlike us, zebrafish have the ability to regenerate motor neurones when they’re damaged. This means that zebrafish can provide scientists with an excellent tool to find out about motor neurone repair. A better understanding how zebrafish achieve neurone regeneration could provide clues to develop new treatment strategies for MND.

From their studies, Dr Becker and colleagues found that a chemical signaling pathway called Notch1 is increased when the neurones are damaged in zebrafish.

By over activating the Notch1 signal, they found that new motor neurones would not grow well, and would not grow in the same prolific numbers as normal. This means that an over active Notch1 signal can stop the regeneration of motor neurones that occurs in zebrafish.

To test whether the Notch1 signal could be counteracted, the research group treated zebrafish with an anti-Notch1 chemical to stop the Notch1 signal. This increased the generation of motor neurones.

As well as having a deeper understanding of the basic biology of how zebrafish regenerate their motor neurones, this study may help to provide new clues for the development of future treatments for MND.

This type of research is vital to lay the foundations for future studies. With a solid foundation of understanding of how motor neurones work, we can work toward identifying new and better treatments for MND.

What does this mean for people with MND?

This work is still at a very early stage of development. It unfortunately doesn’t mean that a treatment coming from this research will be available soon.

Researchers still need to identify whether developing a drug that can stop, or slow down the Notch1 signaling pathway would be a beneficial treatment strategy. To do this, researchers will need to carry out tests in a cellular, and animal models of MND. This is an important step, as it determines whether treatments are safe and effective before testing the treatment in people.

More information:

The Journal of Neuroscience, 29 February 2012, 32(9): 3245-3252; doi: 10.1523/JNEUROSCI.6398-11.2012

Official Edinburgh University news release.

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.

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.

Another recycling bounty hunter linked to MND

In the short space of three months, details of a second gene have been published linking MND to the protein recycling system in our cells.

Leading this research was Prof Teepu Siddique, eminent MND researcher from North Western University in Chicago USA. Not only was he the founder of the first MND causing gene SOD1, but he also led the group that identified faults in the UBQLN2 gene in MND in August 2011. This research was published in the November edition of the Archives of Neurology journal.

We’ve invited Prof Siddique to give a plenary talk at this year’s International Symposium in Sydney, Australia from 30 November to 2 December 2011, at which we believe he’ll be discussing these exciting new advances!

What did they do?
Instead of searching for common genetic mistakes in families with the inherited form of MND, this research group focused on a candidate gene called SQSTM1. They chose SQSTM1 as a candidate due to the prior knowledge that its protein product is associated with MND.

They then unravelled the code for this particular gene in 340 people with the rare, inherited form of the disease and 206 sporadic cases of MND. They also compared these with 738 healthy controls.

They identified 10 different mistakes in the SQSTM1 gene in 15 people and did not find any of these mistakes in the healthy controls. The research group therefore estimate that genetic mistakes in the SQSTM1 gene could account for approximately 2-3% of cases of MND.

However, it is not yet conclusively known whether these mistakes cause MND, or increase the risk of somebody developing the disease. Further studies are therefore needed to confirm this.

What does SQSTM1 do?
The gene SQSTM1, holds the instructions for a protein called P62, otherwise known as sequestosome 1. 

The P62 protein can be thought of as a ‘bounty hunter’ of proteins that need to be recycled inside motor neurones and other cells. When given instructions to find proteins waiting to be recycled, it seeks them out and delivers them to the cells recycling system.

P62 has a related role to ubiquilin 2 (UBQLN2 which we wrote about in August) as they both work in the protein recycling system within the body.

This research therefore further implicates that the protein recycling system is faulty in MND.

The next steps with this story, is for researchers to confirm whether mistakes in the SQSTM1 gene cause, or contribute to the disease in other populations around the world. They will also need to investigate how the protein recycling system can go wrong in MND to be able to develop new treatments that can target these processes to slow down, or stop the disease.

More information on the protein recycling system:
Last month, Prof John Mayer from University of Nottingham, who is the Chair of our Biomedical Research Advisory Panel, took us behind the scenes of the protein recycling system on our research blog

Read our press release.

Reference: Fecto F et al. Arch Neurol. 2011; 68(11):1-7

Fighting a faulty recycling machine in MND, with Prof John Mayer

A recent gene finding suggests that recycling within our cells is key to all forms of MND. This story captivated many people affected by MND and our blog broke its previous record for the number of hits in one week at over 4,000. It was also linked to, as a reliable and informative piece, from a number of worldwide MND/ALS Associations and forums.

Prof John Mayer, University of Nottingham

Due to the popularity of this story, Prof John Mayer from University of Nottingham will be taking you on a whirlwind tour of the recycling process within our cells. Prof Mayer is currently the chair of our Biomedical Research Advisory Panel, which ensures that we fund the most promising laboratory based research projects to investigate the causes, develop treatments and find markers of disease progression.

He’s also been pioneering the investigation of the recycling process within our cells to learn more about neurodegenerative diseases such as MND for the past 24 years. Below, Prof Mayer explains more about how he’s been involved with this story, and where this could lead us in the future:

The beginning…
Twenty four years ago, Prof Jim Lowe and I discovered that pile-ups of proteins in neurones in MND, and other chronic neurodegenerative diseases eg Parkinson’s disease and Alzheimer’s disease, contained ‘tagged’ proteins. We’ve been trying to understand why ever since!

We did it by detecting those tags, and ‘staining’ tissue sections from the brains and spines of patients who had died of MND in Derby and Nottingham to see if we could ‘see’ those piles of proteins in surviving neurones. We did!

From that day on, we knew that the protein recycling system must be deeply involved in neurological disease and that the system must fail or be overwhelmed in the neurones of people with MND.

How it works
Proteins can be thought of as the building blocks of our cells and all proteins are made and broken down continuously –this is called protein turnover. It is essential because faulty proteins can be made or proteins can be damaged in each cell, including neurones. Protein turnover in neurones is vital because the vast majority do not divide – once these cells are laid down we are stuck with them. Any problem protein in a neurone must be removed or it may die.

Proteins are ‘tagged’ for removal by chemically attaching a small protein to them called ubiquitin – actually chains of ubiquitins all linked to one another to create a long ‘tag’ which will be easily ‘seen’ by the machine that will destroy the tagged protein.

The machine is an enormous entity in the cell called the 26S proteasome. The tagged proteins have to be fed into large caverns in the middle of the machine for destruction, with the tags removed first to be used again. The mechanism is called the Ubiqutin Proteosome System of protein destruction in the cell, the UPS for short (and not to be confused with the ‘logistics’ company!).

It just would not do if proteins could be destroyed anywhere in the cell, like by those proteases in biological washing powders, the cell proteins would always be at risk of degradation. So, the destructive sites are hidden inside the proteasome machine, the proteins are tagged and they’re fed inside!

There are also a group of cousins of ubiquitin that transfer the tagged proteins to the proteaseome machine. These proteins have a ‘docking site’ for tags at one end and a different tag at the other end which docks to special sites on the proteasome machine. The transfer proteins seek and find tagged proteins and take them to the proteasome machine where they dock and the tagged proteins are fed in for destruction after removal of the tags.

Ubiquilin 2 is one of the carrier proteins which, when made with errors, has been found to cause MND.

Medical science is most comfortable when there is genetic proof of the importance of a process – the discovery of mistakes in ubiquilin 2 has now done this for us!

Mimicking MND by deleting ‘machine’ genes
We have used modern gene targeting in mice to demonstrate that if we deliberately deleted a gene for one of those proteins in the 26S proteasome machine conditionally in neurones in the brain, so we would not cause problems anywhere else in the body, we could ‘mimic’ different neurological diseases.

The way we did it was to target the neurones that die in Parkinson’s disease and the neurones that die in the second most common cause of dementia after Alzheimer’s disease – dementia with Lewy bodies. This was published in 2008 and our genetic approach worked!

By depleting one of the 26S proteasomes machine parts, in the section of the brain which dies in Parkinson’s disease or dementia with Lewy bodies we caused neuronal death –and there were pile ups of tagged proteins in surviving neurones – a key hallmark of disease.

Implications for the future of our MND research
The MND Association has given a pilot grant of £10,000 to Dr Lynn Bedford, who carried out this work, to see if it is possible to delete the gene in motor neurones and innervated muscles to cause MND. She is still working on this (only one pair of hands!) but the tissue sections are now ready to see if MND can be caused this way. We expect that this will be the case and we should know soon!

Keeping open minded
Research into complex disease needs open-minds and different areas of research. Genetics provide clues to familial disease, like for ubiquilin 2, but families are just a small number of people with the disease. The finding of ubiquilin 2 in pile ups with TDP-43, FUS etc shows the generality of the UPS response in MND and ubiquilin 2 will probably be in pile ups of proteins in the other disease too.

The discovery of mistakes in one gene, ubiquilin 2, whose protein product is involved in protein degradation, is fantastic to try to understand MND and other chronic neurodegenerative diseases but there is much more…

Rare mistakes in the genes for three other proteins involved in protein degradation that cause neurodegeneration have recently come to light. Mistakes in a gene called VCP cause MND and a related disease called frontotemporal dementia, mistakes in a gene called optineurin cause MND and mistakes in the p62 protein gene cause MND.

Lightning generally does not strike in the same place twice, yet alone four times! So, to have mistakes in at least four genes causing MND whose protein products are involved in protein degradation dramatically increases the likelihood that problems with this system are central to neurodegenerative disease.

For general effects in disease, researchers must have a pathway that when misbehaving or overwhelmed causes disease (not to mention to provide a therapeutic target). It is one thing to have the capability to find these genetic errors, but it is another to map out the steps in a pathway(s) that cause disease. If a pathway is identified, like through ubiquilin 2 (and the other three genes plus our other ubiquitin-related work), and in general the UPS in other neurological diseases, then I believe that this pathway should be the focus of investment to try to find a cure.

Putting my money where my mouth is
I published a review in the journal Nature Reviews Drug Discovery on the ‘druggability’ of the UPS for many unrelated diseases. Towards the end I had a ‘dream’: if the UPS could be stimulated then neurodegenerative disease could be controlled.

I could not believe it, but some time later, at the end of 2010, my friend Dan Finley and colleagues answered my dream, at least conceptually. They published in the prestigious journal Nature, work on a drug that activated 26S proteasomes to degrade proteins including some involved in neurodegeneration.

So, what are we waiting for? Answer, all the work that goes into converting an initial discovery into a novel therapeutic approach…Watch this space!

Our final thoughts

The story of the recycling process and ubiquilin 2 is indeed an exciting one that is constantly evolving to provide us with more answers as to what causes MND and how we can fight it in the future. As described by Prof Mayer, ‘the machine’,  the proteasome, is normally part of a well oiled process and it is clear that if spanners are thrown into the works that the system can go terribly wrong and cause a number of neurodegenerative diseases, including MND. It will definitely be interesting to watch this research story unravel its secrets in the future.

One thing is certain though – that keeping on top of recycling is very important!

Chromosome 9 finally reveals its secrets

It’s taken a huge international collaboration, including 3 MND Association-funded scientists, to discover a genetic mistake that appears to cause almost 40% of cases of familial (inherited) MND – that’s nearly twice as many as are caused by mutations in the SOD1 gene and more than three times as many as are caused by TDP-43 and FUS combined. Yet despite the fact that it’s relatively common, the rogue gene proved especially difficult to find.

Digging for genes

Our genetic code is arranged into 23 pairs of subunits called chromosomes. Earlier work had homed in on an area on chromosome 9 that appeared to be significantly associated with both MND and the related neurodegenerative disease frontotemporal dementia (FTD), but nobody could drill down as far as the problem gene itself. As a result, chromosome 9 became something of an ‘archaeological dig site’ for MND researchers, with several groups using cutting edge techniques to try and excavate the elusive causative gene that they knew was lurking somewhere in the short arm of this chromosome. The successful international team, which included almost 60 scientists at 37 institutes, finally discovered the exact location and nature of the aberrant genetic code by looking in the most unlikely of places – in the stretches of DNA that do not actually provide any instructions for building proteins, otherwise known as non-coding DNA.

What did the researchers unearth?

The research team studied DNA samples from a Welsh family affected by inherited MND and FTD that was already known to be associated with chromosome 9, as well as samples from a similar Dutch family and a large number of Finnish inherited and non-inherited MND cases. In among the non-coding DNA in a chromosome 9 gene called C9ORF72, the researchers found a 6-letter genetic ‘word’ which, in healthy individuals, is consecutively repeated up to about 20 times. However, in the Welsh and Dutch families and a large proportion of the Finnish familial cases, the 6-letter word was repeated as many as 250 times. This phenomenon is known as a ‘repeat expansion’. The researchers went on to check for this repeat expansion in familial MND cases from North America, Germany and Italy, and found it cropped up in 38% of them. They even found it in a much smaller proportion of sporadic cases from Finland, suggesting that it could be an important risk factor in at least some people with the  non-inherited form of the disease.

What does the discovery mean for MND research?

Despite the fact that the repeat expansion does not directly affect the instructions for building a protein, there is good reason to believe that it can still lead to significant neuronal damage. At the moment it is not fully understood how this happens, but one possibility is that it leads to the production of excessive and consequently toxic quantities of RNA, the molecule that provides the cell with a more usable copy of DNA. Disruption to RNA processing has already been implicated as a disease mechanism in MND – this is the pathway through which faulty TDP-43 and FUS are thought to exert their effects – so C9ORF72 may provide scientists with another piece of the RNA jigsaw.

The effect of the repeat expansion is clearly open to influence. Among those people with the repeat expansion, some experienced only FTD, others showed only muscle weakness, and some had both MND and FTD.  The reasons for this variation in symptoms will be just one area that scientists will now want to look into. This overlap between MND and FTD is something that researchers are very keen to understand, and the C9ORF72 discovery may be the key to solving this puzzle. They will also want to better understand how the repeat expansion causes damage, and that will include trying to find out what C9ORF72 actually does – at the moment this is unknown. (Maybe it’ll get a more interesting name along the way!) Building on the new finding in this way could help move us closer to an effective treatment.

For now, a more tangible consequence of the discovery could be a genetic test for people already diagnosed with familial MND who want to understand more about the basis of their disease. Such a test will take a little time to develop but should become available in the UK in the next few months. When it does, it will be accessible to genetics labs across the country. Anyone interested should speak to their doctor or specialist nurse.  

Dead heat

Just as archaeologists might question whether a newly discovered artefact is the real thing, so scientists need double-checking when they claim to have made a new discovery. Fortunately, a second team hit upon C9ORF72 at exactly the same time, and their results will be published alongside the work described here, in the journal ‘Neuron’. The race to the ‘Lost Ark’ of chromosome 9 ended in a tie, but has provided the research community with a major piece of the MND puzzle on which to build future discoveries.

Article: Renton A, Majounie E, Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. Neuron (2011).

Read our press release on the C9ORF72 story.

New gene finding suggests recycling is key to all forms of MND

Researchers from Northwestern University Feinburg School of Medicine in America, have identified that faulty ubiquilin 2 plays an integral role to MND.

Led by eminent researcher Prof Teepu Siddique this research group describes unique mistakes in a gene called UBQLN2, which codes for a protein called ubiquilin 2, in five families with the inherited form of ALS. This research group also found that this protein is found in both the inherited and sporadic form of MND, which suggest that this finding could be key to finding a new treatment for the disease. Their findings were published in the prestigious Journal Nature.

What did the researchers do?

The researchers started by identifying a novel genetic mistake in a gene called UBQLN2 for a family affected by the inherited form of ALS. ALS is the most common form of MND. They went on to duplicate this finding by identifying four more genetic mistakes in the same gene in four other families with inherited ALS. This verified that this finding is not simply a ‘one off’.

By examining post-mortem spinal cord samples from people with ALS within these families, faulty ubiquilin 2 was identified as being involved in forming ‘tangled lumps of proteins’ within their motor neurones. When a researcher looks down a microscope at a motor neurone with the disease this ‘tangled lump’ is a classic sign of MND.

The next question that this research group addressed was whether ubiquilin 2 could also be found in other forms of MND. Remarkably, by studying post-mortem samples of people with the randomly occurring ‘sporadic’ form, inherited form (caused by mistakes in SOD1, TDP-43, FUS or an ‘unknown’ gene) and fronto-temporal dementia – related MND, they identified ubiquilin 2 within the ‘tangled lump’ in all of the samples.

This means that ubiquilin 2 could be the ‘smoking gun’ of MND.

Never before has one single protein or gene been related to all forms of ALS. Until now.

Mistakes in this gene are very rare and as yet, we don’t know how many cases of inherited MND are caused by it. This discovery does not open up the possibility of a new genetic test to identify people who might be at risk from the disease, but it does provide a new and exciting insight into the causes of all forms of MND.

How does ubiquilin 2 cause MND?

Imagine a world where all recycling collectors are on strike. Every Wednesday at 7am you place a box of recycling on your driveway ready to be collected, but it’s still there in the evening. The next week you put out more recycling, and that isn’t collected either. After weeks of putting your recycling outside, you notice that the pile is mounting and still isn’t being collected. This doesn’t bother you too much as you can still step over it, albeit in a slightly slower manner. A few months pass and you can no longer get out of your driveway as it’s covered by recycling. Now you can’t get rid of your rubbish, you can’t get to work and you can’t even leave your house all because of the pile up of recycling. The same thing is happening to everybody all over your town. This is what happens in MND.

One of the pathological hallmarks of MND is a build-up of ‘recycling bins’ of proteins in motor neurones. Normally, these recycling bins are emptied on a regular basis by a process regulated by a family of proteins called ubiquitins – of which ubiquilin 2 is a member. This build up of recycling causes pandemonium in cells, as vital movement of nutrients around the cell cannot easily pass to where they need to get to, causing an additional burden to the motor neurones. Eventually, the motor neurones start to degenerate because of this.

What now?

These results will now need to be verified in more people with MND. However, this study could revolutionise the MND research world and provides evidence that the recycling pathway plays a crucial role in MND. Researchers now need to find out how the recycling pathway is involved with MND which could provide insights into how new treatments could be developed to target the disease.

We’ll be keeping a close eye on ubiquilin 2 in the future!

Read our press release on this news story.

Read the Scotsman article on this story.

Reference: Nature (2011) DOI:doi:10.1038/nature10353

UPDATE: Prof John Mayer from University of Nottingham takes you even further behind the scenes of this news story.

Thinking outside the neurone and toward the stars

Neural Progenitor cells, courtesy of Prof Chandran lab, University of Edinburgh

By using spinal cord donations from people with MND, an American group of researchers have created a new, human ‘in a dish’ model of MND. Their results were published in the journal Nature Biotechnology.

Human neuronal progenitor cells, which have the potential to turn into brain cells but not other types of cell, were extracted from post-mortem spinal cords and programmed to turn into living neurone support cells called astrocytes. The research group, led by Dr Brian Kaspar from Ohio USA, is hopeful that these human astrocytes grown in the laboratory can be used to learn more about the causes of MND.

Astrocytes and MND

Astrocytes, so called because of their star-like appearance, have been known to be involved with MND for many years now. Normally, astrocytes support and nourish nerve cells but in MND, they can become toxic to motor neurones, causing them to degenerate. However, before now, there hasn’t been a way to prove that this really does happen in people as it’s impossible to extract these cells while the person is still alive.

Using post mortem samples to find the answers

This research group used post-mortem spinal cord donations from people with MND to create a new, human astrocyte model, grown in laboratory dishes.

They were then able to demonstrate in the lab that these human astrocytes are toxic to healthy human motor neurones, causing them to degenerate. This verifies that astrocytes can cause MND in people, and not just in animal models.

They then went on to show that the healthy motor neurones could be protected if they stopped a protein called SOD1, which can be faulty in MND, from being created. This was found in astrocytes created from a person with a SOD1 form of inherited MND and remarkably, also from astrocytes created from people with the randomly occurring, sporadic form.

Reaching for the stars

By using post-mortem spinal cord donations from people with MND, and thinking ‘outside the neurone’ this research group were able to successfully create a new human ‘in a dish’ model of disease. There are still many unanswered questions left to explore with this new model, such as how the astrocytes cause the motor neurones to degenerate. By understanding more about this process, new treatments could be investigated to stop astrocytes from being toxic and slow down, or stop MND.

Find out more about tissue donation for general research purposes.

Reference:

Published in Nature Biotechnology: doi:10.1038/nbt.1957

Pointing the finger towards the causes of MND

Would it ever cross your mind that the relative lengths of your fingers might be related to the durability of your motor neurones? Probably not – at first glance the link seems extraordinarily tenuous! However, a research group led Prof Ammar Al-Chalabi, who has close connections with the Association, has found that people with MND tend to have relatively long ring fingers.

So what? Well the results of this study, published this week, do in fact provide some important clues about events occurring before a person is even born that might predispose them to getting MND. For both men and women, exposure to relatively high testosterone levels during development in the womb is associated with having a relatively long ring finger compared to index finger in adulthood. Research has already indicated that testosterone might influence motor neurone health, and increased testosterone exposure in the womb is also linked to male sex and athletic prowess, both of which may be connected with a slightly higher risk of MND.

Prof Al-Chalabi’s team therefore took an extremely simple but ingenious approach to finding out that men and women exposed to higher levels of testosterone during their development as a foetus might be more likely to get MND as adults. Although their results will need confirming in larger studies, they are a reminder of how very subtle factors that might start accumulating before a person is even born, let alone during their childhood or early adulthood, can start to tip the balance towards the development of MND in middle age or later.

Most people with MND are likely to ask themselves ‘Why me?’ and it’s very tempting to look for answers in events immediately preceding diagnosis. The results of this study support the idea that some risk factors may have occurred well before a person could possibly have any memory of them!

More information on what this study means for MND research and people affected by the disease is available in our press release.

Download the official lay article from the BMJ

Article reference: Vivekananda U, Manjalay Z-R, Ganesalingam J et al. Low index-to-ring finger length ratio in sporadic ALS supports prenatally defined motor neuronal vulnerability. Online First J Neurol Neurosurg Psychiatry 2011; doi:10.1136/jnnp.2010.237412

Learning about genetic messages and their potential role in MND

Talks on RNA biology are new to the symposium this year as it is the newest puzzle piece to the expanding list of possible cellular causes of MND.

So why is RNA biology important to MND and what is it all about? RNA stands for ‘ribonucleic acid’ and plays a vital role in the creation of proteins that play day-to-day roles in our bodies. Two MND causing genes – TDP-43 and FUS, have been found to have a role in the processing of RNA and so understanding more about the link between these genes and RNA processing is of growing importance in order to find out more about the causes of MND.

So what does RNA processing mean? Our genetic code is over three billion letters long and holds the instructions for how to build everything in our bodies but in this form, it’s nonsense. ‘Editors’ are a type of RNA processers and are needed to copy and ‘tidy’ short sections of code to produce instructions that can then be used to build new proteins. This session was therefore dedicated to our growing understanding of how TDP-43 and FUS may be involved in RNA processing and how this may be affected in MND.

The first talk was given by one of the researchers that we fund– Prof Tom Maniatis from Colombia University in America. In his talk, he gave an enthralling overview of his current study to develop a human ‘in a dish’ model of MND following the success of a recent ‘proof of principle’ study in mice. This new and exciting method of studying live human motor neurones and support cells called ‘glia’ uses stem cell technology to ‘turn back the clock’ on skin cells donated by people living with MND. 

In his current study, alongside Prof Chris Shaw from King’s College London and Prof Siddharthan Chandran from Edinburgh University, Prof Maniatis is studying the effect of a ‘sandwich’ of glia and motor neurones on the amount of proteins being made. The preliminary results from the human study have found that there are hundreds of other genes that are found in higher and lower quantities than normal in motor neurones as compared to healthy motor neurones. Of these, a large number are involved with many different processes that are known to be involved with the degeneration of motor neurones. These findings are still preliminary as the study is ongoing – but it’ll certainly be interesting to find out more in the future!

As the session continued, we heard from a number of speakers who are also working to find out how TDP-43 is involved with RNA processing and how this causes motor neurones to degenerate.

The ‘take home’ message from these talks is that we are learning more about what TDP-43 interacts with through its role in RNA processing, and we are now moving closer to learn how it can cause MND.