Sharing and networking in Liverpool

From Sunday morning to Tuesday evening last week, there was a lot of talk of MND research going on in Liverpool. The reason for this ‘hotspot’ of discussions was due to the annual meeting of an international consortium of MND researchers taking place at the University of Liverpool. The 10th International Consortium on SOD1 and ALS (ICOSA) meeting took place last weekend (4 – 5 March).

In 2001, five laboratories came together to form ICOSA, where the aim was to share knowledge to design better-informed experiments to understand the rare, inherited SOD1 form of MND. MND Association grantee, Prof Samar Hasnain was one of its founding members. Success of this philosophy of sharing knowledge prior to publication has resulted in several leading groups joining the effort, looking at other causes of inherited MND too.

A tradition of ICOSA meetings is to hold an open meeting for sharing latest results with a wider audience, following their closed meeting. Thus, on Tuesday 6 March, an open meeting was held to allow the exchange of the latest results and ideas between ICOSA members and the UK MND research community.

I attended this one day meeting in Liverpool and I’ve written a mini report on the meeting below, including a couple of highlights.

The first few presenters demonstrated the truly international nature of this collaboration – they had travelled from the snowy landscape of northern Sweden, the sweltering heat (at least in August!) of mid-state Florida and from RIKEN, the large natural sciences research centre, in Japan .

The researchers represented were a mixture of physicists, biochemists and neurologists – an unusually broad spectrum of knowledge and speciality for an MND research meeting. Essentially, their core, joint interest was in understanding how the structure of a protein has such a marked change leading to MND developing or the disease progressing.

The structure of a protein is essentially about folding. The correct folding will mean that the protein can do its job. Folded incorrectly the protein won’t be able to work. An example of incorrectly folded protein is the protein clumps or ‘aggregates’ seen within motor neurones in MND. There is a whole chain of events that lead the appearance of these clumps of protein – and researchers at the meeting discussed every step along the way.

How do proteins fold and why is it important?

When the instructions for making a protein (ie genes) are read and edited by DNA and RNA respectively, they are reading or editing instructions to arrange a set of building blocks in a particular order – there are 20 different types of building block – our amino acids. ALL of our proteins within our bodies are made from specific arrangements of this core set of 20 building blocks. The arrangement of the building blocks determines where the protein folds, in which direction and the shape it makes. There are many possible folding arrangements a protein could make, but it will always try and fold itself into the lowest energy shape (a good way to think about this is the shape where the protein is ‘most comfortable’).

Geneticists know a lot about the beginning of the process (what the sequence of building blocks will be) and biochemists and pathologists know a lot about the end of this process (what the protein does and a what it looks like in the cell when it clumps together) – but the physicists of the MND research world are working on the bit in the middle (precisely where which building block is, in the folded protein).

A change to the sequence of the building blocks, as seen in the proteins made from mutated genes that cause MND, will lead to unusual folding, and damage to the cell – due to the loss of normal function or a trigger for toxicity. So having a complete picture of a protein ‘lifespan’ is really important in understanding what goes wrong in MND and how to fix it.

Unravelling questions about SOD1

People with the SOD1 form of the rare, inherited type of MND have a mistake in the assembly of one building block in the instruction to make the SOD1 protein. Over 160 different, single building block mistakes have been found in this form of MND so far. All of them lead to the development of MND. So that means 160 damaging variations in the folding of the SOD1 protein.

Over 70 other delegates and I heard the latest on how mimicking the effects of these mutations (by changing building blocks of the protein) in SOD1 mouse models tells us more about this cause of MND. It’s even possible to study the different effects of the toxic protein on different cell types essential for motor neurone function. (Although motor neurones carry the messages, they are supported by groups of ‘glia’ cells around them).

Where (the) ‘FUS’ is

Prof Larry Hayward presented his research on a protein called ‘FUS’; mutations in this gene causes another form of the rare inherited MND. The damaged ‘FUS’ protein is found in a completely different place in motor neurones than usual. Images of motor neurones where the FUS is in the centre of motor neurones, as usual, looked a bit like fried eggs; but the location of the damaged FUS in the outside of the cell reminded me of ring donuts! By stressing motor neurones, he showed a video of the proteins moving from the centre to the outside of the cell; and back to the centre when the stress was removed. This all happens very quickly, in a matter of minutes!

C9orf72 – a hot topic

Another highlight of the meeting was the presentation by MND Association grantee Prof Huw Morris on both how the C9orf72 gene mistake was found last year, and also on what’s happened since the results of this finding were announced. In the five and a half months since the 21 September announcement, another 26 reports have been published in this area of MND research. That’s slightly more than one report a week! (To put this in context there are roughly 36 MND reports published a week, total, across a broad range of topics). He commented that one factor that kept him focussed in the long search for this gene defect was the people with MND in his care.

Drug scaffolding to correct damaged folding

Above I mentioned that the physicists work out the precise folding of proteins, knowing where each of the building blocks is within its final shape. They do this by isolating the protein they want to study and placing it in increasingly high concentrations of salt solution to remove literally every molecule of water, until the protein itself comes out of solution and forms crystals. These crystals are then analysed by x-ray crystallography and other analytical chemistry techniques.

For a protein made from a mutated SOD1 gene, x-ray crystallography studies found a hole in the protein folding that may explain why it forms clumps within motor neurones. MND Association funded researcher Dr Neil Kershaw from the University of Liverpool presented the latest results from his research in designing a drug that will ‘prop up’ incorrectly folded SOD1, in the hope that this will remove its damaging effects.

I hope that this report demonstrates that in between the ‘big news’ stories about MND research, steady progress continues to be made in understanding MND and searching for treatments for it.

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.

Breaking news: new gene identified as a cause of inherited MND

Research published today in Neuron has identified that mistakes in a gene called VCP can cause an inherited (familial) form of MND.

This is the third gene this year that has been identified as a cause of familial MND which really shows the ‘snowballing’ speed that genetic research is taking. Read about this on our press release:  http://bit.ly/dXcjE4

Research paper:   Johnson JO et al. Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS . Neuron  (Vol. 68, Issue 5, pp. 857-864)

Three new projects, three steps closer to a world free of MND

Next month will see the start of three new Association-funded research projects that will each move us closer to achieving some of the key targets set out in our research strategy. They involve recently discovered genetic causes of MND, new disease models and a novel way of measuring the progress of the disease – all very exciting stuff! You can read more about the projects here.

The three research teams involved are embarking on their new investigations just as Marion and Natasha are busy preparing for next month’s Research Advisory Panel meeting, where more applications for funding will be assessed. The MND research machine never sleeps!

The importance of FUS

It is really quiet in the office today, with a few colleagues out and about for various reasons. As soon as the thought entered my head about having a productive day with no distractions, an email landed in my In Box. Had I seen the research report mentioned in this press release? A quick scan of the release and my thoughts were ‘no’ (I haven’t seen it), ‘how exciting’ and ‘well there goes my quiet afternoon’ in quick succession!

The bottom line of the research is that some MND researchers in Chicago, USA led by Dr Han-Xiang Deng and Professor Teepu Siddique have been able to make a connection between a biochemical pathway recently implicated in the rare, inherited form of MND (known as familial MND) and sporadic MND. They have found clumps of the ‘FUS’ protein in motor neurones of people with familial MND AND in motor neurones of people with sporadic MND too.

One of the keys to understanding what causes motor neurones to die in MND is to understand which proteins are deposited in affected motor neurones. Deposits, or clumps, of proteins are common to many neurodegenerative diseases, the main difference between the diseases is which proteins are found. A protein called TDP-43 was the first protein discovered to be consistently deposited in the motor neurones of people who had MND. The results from this Chicago research group showing that FUS protein accumulates in most cases of people with MND is the second discovery of its kind.

The efforts of many people around the world will now be focussed on confirming these exciting results which take us closer to understanding the causes of MND.

All of these studies have been conducted using the post-mortem brain and spinal cord tissue of those that have donate these tissues for research after their deaths. A big thank you to anyone who has helped this happen for close family and friends. More information on this generous opportunity to help MND research can be found on our website.

New genetic cause of MND suggests cellular ‘traffic jams’ may play a role in all forms of MND

As the afternoon was drawing to a close in the office yesterday, we learnt of an exciting new MND research paper that had been published in the prestigious journal, Nature. The research suggests that a rare mistake (mutation) in gene called ‘Optineurin’ (OPTN) can cause MND and they also suggest that OPTN may be involved in causing the disease in all forms of MND.

After reading the abstract, which provides a brief overview of what the researchers found, we wanted to know more. However, the way that some journal articles are accessed –including this one, is a bit like a locked novel. You can freely read the blurb of the book (the abstract) but to get the nitty-gritty details involves either asking the author for a copy, or by paying £30 for access. We decided to email the researchers as our first port-of-call to ask them if we could borrow a copy. As the researchers are based in Japan and are many hours ahead of us, we then had to wait patiently until this morning to find out whether in their working day they had obliged. Luckily for us, the researchers were extremely generous and speedily provided us with the paper for free so that we could explain what they did and what they found to all of you!

Overall, the researchers studied the genetic spelling differences of 16 people from close blood relative marriages – so called ‘consanguineous marriages’, 76 people with the inherited form of MND, and 597 people with the randomly occurring sporadic form of the disease.

From this they identified eight people with mutations in OPTN, seven from close blood marriages and one from a sporadic case. To make sure that the gene mistakes were not a ‘common’ spelling error that happens by chance, they also checked their results against controls who did not have the disease. They could not find the spelling difference in any controls and  it is likely to be the cause of the disease for these people.

However, if we dig a little deeper into this research, the story is not just about identifying a new genetic cause of the disease for some families. It was more about finding out what goes wrong on a cellular level which may give us more clues about what causes the disease for all types of MND.

By studying what goes wrong on a cellular level, the researchers were able to find out that MND may be triggered by a loss of function of OPTN, where it plays an important role in the trafficking of substances around the cell and indeed out of the cell. It also plays an important role in regulating cell death.

Further to this, the researchers also found that OPTN is faulty in both cells that are affected by SOD1 mistakes as well as TDP-43 mistakes (two previously identified genetic causes of MND). As the product of these gene mistakes are usually never found together, OPTN may be a more general ‘marker’ for all types of MND.

This is exciting research and we look forward to seeing more research into OPTN in the near future. To find out more information on this research finding, keep an eye out for a new ‘news in research’ article on our website. Or, you can read the scientific abstract on the Nature website.

As you may already be aware, identifying the causes of MND is one of our research priorities as set out by our research strategy. We are funding a number of projects – including a major international research collaboration that is hunting for genes, to learn more about the causes MND.

To let us know your thoughts on this research finding, please leave us a comment below by clicking on the orange ‘leave a comment’ button below the post.