How is tissue donation helping us to solve the MND puzzle?

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

Last year, I wrote about our trip to a brain bank. Here, we learned about how people can arrange to donate their tissue (brain and spinal cord) to tissue banks after they die, and how it is stored and used in MND research all around the UK.

What you might be asking is: what can tissue actually tell us about MND, and how will this help us find new treatments?

To find new drugs that can beat this disease we first need to understand what is going on in the brain, which is very difficult to study in living people. This is why post-mortem tissue from people with MND is an invaluable resource. Below are four reasons why tissue donation is so important. Continue reading

Collaborating across Europe to find a cure: ENCALS 2016

332 delegates, 135 posters, 41 talks, one goal: to cure ALS

The European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) was set up to find a cure for ALS/MND by working collaboratively across 35 research centres (universities and hospitals) throughout Europe.

The 14th meeting of ENCALS took place in Milan between 19-21 May and was attended by scientists and doctors from across Europe. Researchers from the USA and Canada were also invited to present at this meeting.

Presentations on day one of this year’s meeting looked at some of the techniques to help identify genetic changes (mutations) linked to MND, such as whole genome sequencing. This is a rapidly growing area of research, thanks to Project MinE  – a global effort to find MND causing genes.

Clinical research was the focus on day two, and discussed the latest imaging and biomarker research. This is an important area as it will offer new ways to help track the progression of MND, and help to speed up diagnosis of this disease. Continue reading

Visualising FUS

Prof Vladimir Buchman (Cardiff University) was awarded funding by the MND Association for his research into the fused-in-sarcoma (FUS) protein. Dr Tatyana Shelkovnikova began the project in April 2014. Find out more here.

“For the MND Association’s blog a day we have this very nice (we think it is nice!) collage illustrating how FUS aggregates (green) gradually develop in cultured cells expressing a mutant form of this protein -enjoy the image!”

fus image

Continue reading

What’s all the ‘FUS’ about?

Prof Vladimir Buchman (Cardiff University)’s research was selected as one of the best research studies, as decided by the journal editors, published in the Journal of Biological Chemistry in 2013. He is building on this research in his Association-funded project, which began on 1 April 2014.

The background to FUS:

In 2009 an international team of scientists, including researchers funded by the Association, identified the FUS gene as a cause of approximately 4% of inherited MND cases (5-10% of total MND cases).

The FUS protein formed by this gene is usually found in the nucleus or ‘control centre of the cell’. A change in the structure and/ or function of the FUS protein leads to motor neurone damage and the development of MND. This change causes the FUS protein to ‘wander’ outside of the cell nucleus and form protein ‘clumps’ within the cell.

These protein clumps, as well as being found in 4% of inherited MND cases, are found in many cases of MND and the related disease, frontotemporal dementia. At present it is still not clear how this happens and how these clumps of FUS protein cause MND.

Continue reading

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.

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.

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.