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

New genetic discoveries tell us more about what causes MND – Part 1

Today some exciting news about the genetics of MND was published in the scientific journal Nature Genetics. The results come in two research papers published in the same issue of the journal.

This blog post discusses the results of the first of these papers for which King’s College London based Professor Ammar Al-Chalabi was one of the leading researchers. A post on the second paper will follow later.

Here we’ve given an overview of what the researchers have found, what it means for people with MND and how the analysis was conducted. You can read a more detailed explanation of the research results from the King’s press release. Continue reading

Professor Ammar Al-Chalabi wins prestigious prize

Huge congratulations to Professor Ammar Al-Chalabi for winning the prestigious Sheila Essey Award at the American Academy of Neurology (AAN) research conference taking place in Vancouver, Canada.

Professor Al-Chalabi is an MND Association funded researcher and Professor of Neurology and Complex Disease Genetics at King’s College London. He is also the Director of our MND Care and Research Centre at King’s.

The Sheila Essey Award is jointly given by the AAN and the ALS Association in the USA, and recognises an individual who has made significant research contributions in the search for the cause, prevention of, and cure for amyotrophic lateral sclerosis (ALS, a type of MND).

Prof Al-Chalabi is receiving the award for his role in helping us learn more about the complex causes of MND, including the role of genetics in the non-familial form of MND.

“It is a wonderful acknowledgement of the work the present and past members of my team have done in ALS/MND research,” Prof Al-Chalabi said. Continue reading

Janine Kirby: My 20 years in MND research

Janine Kirby is a Non-Clinical Reader in Neurogenetics and is celebrating 20 years in motor neurone disease (MND) research this month. Here she tells us more about how she got into the field, her current projects, what it’s like to work at Sheffield Institute for Translational Neuroscience (SITraN) and to meet families affected by MND.

Dr Janine Kirby

Dr Janine Kirby

How and why did you get into MND research?

Having completed my PhD at University College London, I wanted to apply my knowledge of genetics to medical research. I subsequently joined the MND Research Group at the University of Newcastle-upon-Tyne, headed by Prof Pamela Shaw, looking at the frequency of genetic changes in the SOD1 gene in MND patients from the North East of England.

Since then, firstly at Newcastle and then at the University of Sheffield, I have provided genetic input to the research strategy of investigating the molecular basis of this complex genetic disorder. I am now a Reader in Neurogenetics at SITraN working not only on the genetics of MND but also using a method termed transcriptomics (basically which genes are being switched on or off, and by how much) to discover biomarkers for the disease and to understand why the motor neurones are dying.

20 years later I’m still here because it’s incredibly challenging and interesting research, with the opportunity to work with great colleagues and collaborators across the world. Continue reading

Brussels sprouts poster prize stars

A few days before Christmas, I hope that you’ll forgive the obvious pun. Rather than the small green vegetable that you either love or hate, here I’m talking sprouts of new shoots of talent shown by the winners of the poster prizes. They were chosen from over 300 poster presentations at the International Symposium on ALS/MND held in Brussels at the beginning of December.

It was the second year that poster prizes were a feature of the conference. The purpose of the prize was three-fold: to increase the profile of the poster sessions of the meeting; to recognise the quality of the work presented there and to reward presenters of outstanding work. Continue reading

Our DNA Bank: the times they are a changing..

DNABankLogoThis autumn sees an exciting new development in the MND Association’s DNA Bank. Researchers can now use the samples within it to understand why motor neurones die as well as what the triggers are for MND.

How the DNA Bank began

Beginning in 2003 and running until 2012, approximately 1,500 people with MND, 1,000 healthy ‘controls’ – often the partner or spouse of someone with MND – and a further 500 members of families affected by MND gave a blood sample to help researchers understand more about the genetic causes of MND.

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The UK Whole Genome Sequencing project

Dr Samantha Price is the Research Information Co-ordinator at the MND Association. As well as organising the ‘blog a day’ during MND Awareness Month she also communicates the latest news about MND research. Here she blogs about the MND Association’s announcement of the UK Whole Genome Sequencing project.

It’s been a brilliant Awareness Month with blogs about zebrafish research and streaking meerkats. To end on a positive research note, we’re delighted to announce that we are funding a UK Whole Genome Sequencing project to help us understand more about the causes of MND. Utilising samples from our own UK MND DNA bank; researchers in the UK will aim to sequence 1,500 genomes to help identify more of the genetic factors involved in the disease.  Continue reading

Tilting the scales

We know that in the 5-10% of cases where there is a strong family history of MND, there is likely to be a genetic cause at work, acting like a weight to push the scales in favour of the disease occurring.  These gene mutations are hidden somewhere within the 15 billion or so letters of DNA that make up our genome and, through collecting samples from extended families affected by the disease, coupled with huge advances in gene-hunting technology, researchers have managed to identify over two-thirds of the causes of hereditary MND in recent years and are hot on the heels of the other causes.

scales

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Discussing MND in Dublin

Delegates to last weekend’s ENCALS (European Network for the Cure of ALS) meeting in Dublin were met with uncharacteristic hot and sunny weather – enjoyed by the numerous Stag and Hen parties wandering the city centre, but not by the 200 people ensconced in the impressive, new Biomedical Sciences Institute at Trinity College, from 8am to 7pm, for a packed programme of presentations and debate.

ENCALS was established to help develop the standards of clinical and biomedical MND research across Europe and create a more collaborative environment for researchers, industry, funding agencies and Patient Associations. However, the meeting had a very transatlantic flavour, thanks to the participation of several of the leading researchers from North America.

With around 40 speakers, as well as numerous poster presentations, there is too much to cover in a few hundred words, so I’ll focus on just a few of the key themes that were covered. I also apologise for the quite technical language, which may make for hard reading, but is a positive in that it reflects the increasing complexity and sophistication of MND research.

Can we block the ‘molecular funnel’?

The opening speaker, Prof Teepu Siddique, from Northwestern University in Chicago, spoke on The molecular funnel of neurodegeneration. His view of MND is that it may have a large number of different causes, but the way a motor neurone dies will probably be similar, no matter what the original cause. We’re currently finding lots of new genetic factors involved in the disease, but we don’t understand how many of these genes work in health, much less how they malfunction in disease. So, the mouth of our funnel is getting wider.

Prof Siddique’s view is that by focusing on the cellular changes that are common to all forms of the disease, it gives us possible therapeutic targets that could be relevant to all forms of MND. It’s easier to block the funnel at its narrowest point.

He discussed how the degradation of incorrectly formed or damaged proteins is a classic hallmark of all forms of MND. While the way in which the proteins are damaged may differ from one form of MND to the next, it’s the cell’s inability to correctly deal with these proteins that may be a good target. If we can normalise or improve this process, it may keep the motor neurones functioning for longer.

Prof Orla Hardiman, the meeting organiser from Dublin, discussed the need for much larger and more detailed study of large numbers of patients, to attempt to unpick the environmental influences that undoubtedly exist.

A question that many people often ask is whether MND is occuring more often in younger people that in the past. Intriguingly, Prof Hardiman’s ‘population-based’ research using the Irish MND Register suggests the opposite – the average age of symptom onset is getting older. She suggests that continued improvement in medicine and diet means that the population in general is healthier, so our ‘biological age’ is slowing. If age-related diseases such as MND are linked to ‘biological age’ rather than ‘actual age’, it would explain this surprising trend.

Good Genes/Bad Genes

While factors that cause or predispose towards MND are clearly the subject of intensive research, there is of course also interest in factors that might prevent or slow the disease. Some of these potentially ‘good’ genetic variants are being explored:

  • Prof Wim Robberecht’s group (University of Leuven) is examining the function of a gene called ephA4, which appears to correlate with longer survival in humans. This work is supported by studies in zebrafish and mouse models of MND.
  • Prof Kevin Talbot (University of Oxford) showed data that suggests that by increasing activity of a gene called smn1 might be beneficial to motor neurones. This is a strategy that is being followed for a predominately childhood motor neurone disease called Spinal Muscular Atrophy, so if these approaches work in this particular condition, they might be of benefit in other, adult onset motor neurone diseases.
  • Prof Robert Brown (University of Massachusetts) presented early data from a study of a variant in a gene called sarn1, which appears to protect motor neurones from damage….at least in fruit flies and mice. Work is ongoing to see whether it also has relevance in humans.

In contrast, Dr Andrea Calvo (University of Torino) provided information from Italian patients confirming studies in other populations that a variation in the unc13A gene can speed up disease progression.  However, the important issue about these disease-modifying genes – and it doesn’t matter whether they speed up or slow down MND – is that they all represent potential therapeutic targets.

Not just about the motor neurones!

We know that motor neurones do not die alone. Other parts of the brain and spine can be affected, but it’s the motor neurones that ‘bear the brunt’. 

Dr Sharon Abrahams (University of Edinburgh) provided an excellent overview of the range of cognitive and behavioural changes that can occur in the disease, indicating damage to other part of the brain, in particular the frontal lobe. Thankfully, the ‘real world’ effects of frontal lobe changes are usually subtle, but the fact that they can be picked up by psychological tests and MRI scans will help in defining specific ‘subtypes’ of MND which may require additional approaches to managing the disease.

Dr Martin Turner (University of Oxford) outlined evidence from a number of clinical research studies, including his own that nerve cells, called interneurones, might be involved early in the disease. These particular neurones usually play a role in calming down motor neurones, so if they are damaged or lost, the motor neurones themselves become over-excited and stressed, which leads ultimately to their degeneration.

Dr Turner’s evidence comes mainly from clinical imaging and electrophysiology studies in MND patients, but his theory was supported by a presentation from Dr Tennore Ramesh (University of Sheffield) who works with zebrafish models of MND. He showed results using zebrafish that carry a human SOD1 gene known to cause MND. The fish develop a form of MND in adulthood, but the very earliest signs of nerve damage actually occurs in specific types of interneurones that connect with the motor neurones, with the motor neurone damage occurring much later, closer to the onset of symptoms.

Presentations also covered the role of non-neuronal support cells, such as microglia and astrocytes, both of which have been the subject of extensive research in recent years, as they appear to play a role in the speed of progression of the disease. Prof Jeff Rothstein (Johns Hopkins University) introduced a new cellular player to the MND field, called the oligodendrocyte. These specialised cells have been known for many years to play a role in helping neurones to carry electrical signals, as well as helping them to maintain energy levels. Although they are known to be involved in multiple sclerosis, they hadn’t attracted much attention in MND.

Prof Rothstein showed that in human post mortem MND brain tissue, there is evidence that the brain has been making oligodenrocytes. This is certainly very clear in SOD1 mice, where  a massive production of new oligodendrocytes occurs. However the total number of these cells was not increased in the mice, suggesting that older oligodendrocytes were being killed and getting replaced.

He suggested that the new ‘immature’ oligodendrocytes are not nearly as efficient in their supporting role, especially when it comes to supporting motor neurones in maintaining their energy balance. This provides two possible treatment approaches – either try to keep the existing oligodendrocytes healthier or find a way of making sure that their replacements reach their full functional maturity.

I’ve no doubt we’ll be hearing a lot more about these cells in the future.