Families for the Treatment of Hereditary MND (FaTHoM)

Scientists from the University of Oxford have set up ‘Families for the Treatment of Hereditary MND’ (FaTHoM), an initiative to bring together the community of families affected by inherited forms of MND. Their first meeting will take place in Oxford on Tuesday 18th April.

Most people living with MND cannot identify a relative who has also had the condition. However, around 5% of people with MND will have a family history of the disease, which is known as inherited or familial MND. This happens when a single faulty gene is passed down from parents to their children across number of generations.

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New genetic discoveries tell us more about what causes MND – Part 2

Two sets of MND genetic results were published yesterday. One of these results was about the importance of a new gene called NEK1. The second highlighted the role of gene C21orf2 in MND – we wrote an article about this yesterday. Both sets of results were published in the prestigious journal Nature Genetics.

What are the results and what do they tell us?

Researchers found that variations in the NEK1 gene contribute to why people develop the rare, inherited form of MND. Variations in the NEK1 gene were also found to be one of the many factors that tip the balance towards why people with no family history develop MND.

NEK1 has many jobs within motor neurones including helping keeping their shape and keeping the transport system open. Future research will tell us how we can use this new finding to target drugs to stop MND. Continue reading

Identifying the genetic causes of MND in specific populations

Dr Russell McLaughlin from Trinity College Dublin is one of our Junior Non-Clinical Fellows.

Our Non-Clinical Fellowships were awarded for the first time last year. They aim to retain and develop early and mid-career MND researchers conducting biomedical research. These fellowships are funded for up to four years. We are currently funding two junior and two senior fellowships.

In this three-year research fellowship, which began in January, Dr McLaughlin is studying the more subtle genetic causes of MND (our reference: 957-799).

Why is genetic research important in MND?

We know that for approximately 5-10% of people living with MND, the cause of the disease is primarily due to a mistake within the genes. We also know that very subtle genetic factors, together with environmental and lifestyle factors contribute to why the majority of people develop the disease.

It is likely that these subtle genes are quite rare, and that is why we have not found them so far. As part of his research, Dr McLaughlin is hoping to identify the rarer gene variants that may be linked to MND. Continue reading

Using fruit flies to understand a genetic cause of MND

Mistakes in a gene known as ALS5, or spatacsin, cause a rare form of inherited MND that develops at a much earlier age than most other forms of the disease. Under supervision from Dr Cahir O’Kane, MND Association funded PhD student Alex Patto has been using fruit flies to understand how mistakes in spatacsin cause MND (our grant reference 861-792).

Prior to this research, which is based at the Department of Genetics at the University of Cambridge, nothing was known about how faulty spatacsin leads to motor neurone degeneration. Three and a half year years on, this research has shed light on this important question.

What did they find?

By conducting tests in the fruit flies, Alex has found that the spatacsin protein has a role in cell recycling (also known as autophagy), a process which keeps cells healthy. When the spatacsin protein is faulty it leads to disrupted cell recycling and abnormal levels of another protein called Rab7, which might contribute to MND development. Continue reading

More clues to the inner workings of the C9orf72 gene

Continuing the ‘gene hunting theme’ on from our last blog post on Project MinE, a recently published study has shed more light on the C9orf72 gene mutation.

The C9orf72 gene mutation is the most common cause of the rare inherited form of MND (about 40% of all people with inherited MND have this mutation). Some people with the sporadic form of MND also have this mutation, and it has been linked to the development of a type of dementia called frontotemporal dementia (FTD).

Figuring out the normal function of C9orf72

A study by Jacqueline O’Rourke and colleagues at Cedars-Sinai Medical Centre in Los Angeles used mice that lacked the equivalent gene to C9orf72.

When this gene was absent, the mice developed normally and their motor nerve cells were unaffected.

From this evidence they discounted one of theories about the C9orf72 mutation – that a change to the gene stops it working entirely and that this affects the health of motor neurons. Continue reading

Looking for MND genes: Project MinE update

Project MinE is an international genetics project that is analysing DNA from people with MND in detail.

For the majority of people with MND, the disease appears ‘sporadically’ for no apparent reason. For a small number of people, approximately 5-10% of those with MND there is an inherited link, in other words the disease runs in their families.

We know a lot about the genes that are damaged in the rare inherited forms of MND. We also know that very subtle genetic factors, together with environmental and lifestyle factors contribute to why the majority of people develop the disease. These subtle genetic factors are very hard to find.

The goal of Project MinE is to find the other genes that cause inherited MND and help us find out more about these subtle genetic risk factors.


Project MinE was born when Dutch entrepreneur Bernard Muller challenged his neurologist to do something with all the DNA samples in his freezer – samples being stored there for future analysis. ‘Why can’t those samples be analysed now?’ was his question. That was two years ago! Continue reading

Baking with proteins, mRNA and DNA

Today marks the start of MND Awareness month 2014 and our MND Research ‘blog a day’. Before we post our first guest blog we thought we’d set the scene by reminding you about genes and proteins.

As our fundraising campaign ‘Bake it!’ is back for 2014, we thought we’d re-blog our ‘baking with proteins, mRNA and DNA’ in order to help bake MND history!

Thank you for reading our ‘blog a day’ this Awareness Month. We would gratefully appreciate your thoughts and feedback via this short 2 minute survey.

MND Research Blog

Each and every one of us is made up of thousands of different ingredients, which all combine together to create something amazing; life. Perhaps the most important of these are proteins.

Each protein in the body has its own special job to do. From making our muscles contract to controlling blood sugar, proteins are an essential ingredient in life.

In MND research we have identified a number of MND causing genes. These are genes that are found to be mutated in some people living with MND, which somehow causes the motor neurones to die. But, how does this happen? How does a gene form a protein? This blog post explains how an MND causing gene becomes a protein.

As simple as baking a cake

Here at the MND Association we love our cake. So, I thought what better way is there to describe how we make proteins?

cheesecake cheesecake

Every cell…

View original post 631 more words

Same disease.. two very different mice!

The exact course, duration and rate of progression of MND often varies greatly from person to person; even when there is a known family history of the disease caused by a specific MND-causing gene (eg SOD1).

This same variability also occurs in mice. Researchers, funded by the MND Association, took two mice with the same SOD1 gene mutation from two different families (strains). By using these two mice the researchers identified a number of key changes in motor neurones that differ between fast and slow progressing forms of the disease.

Two mice… One gene

The SOD1 mouse

The SOD1 mouse model has been one of the most important MND research tools for scientists

Developing new disease models enables us to both understand the causes of MND and test potential new therapies.

Mice are commonly used in MND research and for the past 10 years or more, the SOD1 mouse model has been one of the most important research tools for scientists working in the field, particularly with testing potential new therapies.

Research published in September 2013 was carried out in a joint collaboration between Dr Caterina Bendotti (Mario Negri Institute for Pharmacological Research, Milan Italy) and Prof Pam Shaw (University of Sheffield, UK).

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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.