MND Research in 2012

Word cloud from our 2012 blog posts. Created from wordle.net
Word cloud from our 2012 blog posts. Created from wordle.ne

At this time of year, it’s always good to look back on the previous year to see just how far we’ve really come. We’re pleased to say that 2012 was full of progress being made in the world of MND research and we hope that the speed and number of exciting findings being announced continues at this pace in 2013.

In 2012, 1,466 scientific papers were published in MND, which is 200 more than the previous year, demonstrating the energy and speed at which progress is being made.

Twitter: If you follow us on Twitter, then we’d like to take this opportunity to thank you for your re-tweets and mentions throughout 2012 to help raise awareness of MND and to keep your friends and family up-to-date with our exciting news. We managed to double our followers in 2012 because of your continued support!

News stories:

We wrote over 30 blog articles in 2012 to take you behind the scenes of MND research. These were viewed over 36,000 times with visitors coming from 126 countries. Here’s an over of a few of the findings we wrote about in 2012:

Clinical trials

At the start of the year, we heard some exciting news that a drug called Cogane produced some encouraging results in an MND Association funded study. A few weeks ago we heard an update that the drug company who owns Cogane called Phytopharm are moving toward a clinical trial and are currently securing funding and support for this. This could  take a number of months before final plans are made but it’s positive to see that MND Association funding has led to this exciting development!

It was also positive to hear some encouraging NP001 clinical trial results for MND, which is leading toward a larger Phase III study to test the effectiveness of this drug in MND in America this year.

Angiogenin findings advance our understanding of MND

In June, we heard that Irish Angiogenin research lead to promising results. One finding was related to a new biological finding of the vital role that angiogenin plays and the second expands on this work and led to the testing of angiogenin in mice that model MND. Later on in the year, we also heard how University of Bath research showed how angiogenin affects motor neurone survival.

New genes

We also heard about some exciting findings in understanding how genes can influence survival and cause MND for some people. In July, Profilin1 was identified as a cause of MND. In our blog, we explained that Profilin 1 has a role in holding the shape of the cell through the cells scaffolding – called the cytoskeleton. We then heard about another gene called EPHA4 which influences survival in MND.

EPHA4 also plays a role in the cytoskeleton which means that researchers can explore this pathway in more detail as it, in conjunction with the Profilin 1 finding, suggests that this guidance/growth system of motor neurones may play an important role in the development of MND.

Advancing our understanding of C9ORF72

Since the discovery that a repeat expansion in the C9ORF72 can cause MND in 2011, researchers have been working to understand more about it. We announced that we would be funding a new Fellowship which aims to explore how C9ORF72 causes MND using our DNA bank samples. Very late in 2012, we also heard that MND Association funded researchers had identified the structure of C9ORF72 repeat, which looks (with some artistic license granted) surprisingly like a Battenberg cake! It will be interesting to see this field of research continue to yield exciting developments over 2013 and beyond.

TDP-43 research in yeast

TDP-43 was identified as a cause of inherited MND for approximately 4-5% of people with a positive family history of the disease in 2008. Since then, researchers have been working to identify how this gene can cause MND and how this system could be targetted to develop a new treatment for MND. In November, we wrote about a study which marked the first steps in the identification of a treatment that can target TDP-43, which is found to clump together in over 90% of cases of MND. Using a novel yeast model, the research group identified that they could reduce the toxic effect of TDP-43 as a potential therapy for MND.

As this is the beginning of the story of TDP-43 specific treatments for MND, it will inevitably be a long journey to answer these questions and to bring treatments to the doctor’s prescription pad. However, it is positive that this research is moving forward and that we are moving in the right direction.

Symposium 2012

One of the highlights from our year is always our International Symposium on ALS/MND. It’s an accumulation of over a year’s worth of work for our Research Development Team and is a fantastic platform that really demonstrates how far research has come in a year.

For our 2012 International Symposium on ALS/MND, we received 419 high quality overviews of research (called abstracts) from across the globe, totaling 172,581 words!

Over 900 researchers, clinicians and healthcare professionals from 30 countries attended our sympsoium in Chicago USA in 2012 to hear 86 platform presentations and to see over 300 poster presentations.

To keep you up to date with news from the symposium, delegates used the Twitter hashtag #alssymp. In total, 950 tweets were sent using this hashtag!

We also blogged live from the symposium to bring you news as it broke, we summarised these findings in our Symposium highlights 2012. There’s still time to share your thoughts about our symposium blogging to assist us with plans for 2013! To take part, please visit www.surveymonkey.com/s/alssymp.  We will be closing this survey on 31 January.

Thank you!

For following news from the ever changing world of MND research on the MND Association’ research blog, we would like to thank you! We hope you enjoy reading our blog posts in 2013 and help us to raise awareness of MND and the pace of research by sharing our news stories with your friends and family!

University of Bath research shows how angiogenin affects motor neurone survival

Published in the prestigious journal Nature Communications and funded by the Wellcome Trust, University of Bath researchers looked closely at the structure of 11 mutated angiogenin proteins, and how changes in their structure influenced activity, function and survival in motor neurones.

Dr Brian Dickie, Director of Research at the Association, said “The researchers at the University of Bath have skilfully combined aspects of biology, chemistry and physics to answer some fundamental questions on how angiogenin can damage motor neurones. It not only advances our understanding of the disease, but may also give rise to new ideas on treatment development.”

Mutated forms of the gene editing protein, angiogenin, are known to cause MND in some families affected by the inherited form of the disease. This is due to a mutation in the normal angiogenin gene (a mistake in the instructions for making the protein) that leads to the production of a faulty/mutated angiogenin protein.

This new research expands on our knowledge of angiogenin, as back in June this year angiogenin, was identified by Irish researchers as playing a vital role in motor neurones with the effects tested in a mouse model of MND.

Creating images with x-rays

University of Bath researchers used a technique known as x-ray crystallography (a method that uses x-ray light to produce highly detailed images of the structure of a protein). Using this technique they were able to view the structure of angiogenin, and 11 angiogenin MND mutants, in exquisite detail. Specifically the researchers looked at the active site (where all the action happens) for changes that may affect the function and activity of the mutated proteins.

These x-ray crystallography images show stunning structural differences in the angiogenin MND mutant proteins, particularly around the active site, and the researchers found that these structural changes caused the mutated angiogenin proteins to have varying levels of activity.

Dr Vasanta Subramanian, who was involved in the research, said: “We hope that the scientific community can use this knowledge to help design more drugs that will bind selectively to the defective protein to protect the body from its damaging effects.”

An MND Association funded study has also used this technique of x-ray crystallography to look at the structure of mutant SOD1 proteins, which are another cause of inherited MND. Under the leadership of Prof Samar Hasnain, Dr Neil Kershaw is also one step ahead and is examining potential drugs to ‘mend’ these abnormal SOD1 proteins. This shows how this type of research, investigating structure and activity of the mutated proteins, can influence the development of new drugs.

What happens to angiogenin in the cell?

As well as changes in the activity of the protein the structural changes cause the angiogenin MND mutants to lose their function, leaving a protein sitting around in the cell, unable to do anything! The researchers found that it is essential that angiogenin is transported from the cytoplasm to the nucleus of the cell in order for the protein to function properly. This is an important step during the process in which proteins are made, if this does not occur then the protein will not function properly. In the angiogenin MND mutant proteins this does not occur correctly with either none, or very little, angiogenin being transported to the cell nucleus. This means that the angiogenin MND mutant proteins do not function properly compared to the normal angiogenin protein.

Stress Granules

The University of Bath researchers also found that the angiogenin MND mutant proteins prevented the motor neurones from producing ‘stress granules’. These are little packages that appear when a neurone is under stress, such as when low oxygen levels occur. When this stress factor occurs they release their contents to protect the motor neurone from damage.

These stress granules are the motor neurones natural defence mechanism. Without these granules the cell’s natural defences are lost and this influences the survival of the cell.

In Summary

This research gives us an important insight into how MND mutations affect the normal structure and function of angiogenin in motor neurones in some inherited forms of the disease. This not only advances our understanding of the disease, but may give rise to new ideas on treatment development in the future.

University of Bath press release

Journal article

Research we fund

Irish angiogenin research leads to promising results

Angiogenin was discovered as a cause of MND for a small number of families affected by the inherited form of MND in 2006. Since then, research has been ongoing to better understand the role of angiogenin and to see if we can use this information to develop future treatments.

This week, we learnt of two inter-woven news stories related to angiogenin. One was related to a new biological finding of the vital role that angiogenin plays and the second expands on this work and led to the testing of angiogenin in mice that model MND. Prof Jochen Prehn leads the Irish research group who made these findings from Royal College of Surgeons in Ireland.

Angiogenin to the rescue!

Through their research, the Irish group identified that angiogenin acts as an emergency service call from our motor neurones to support cells. The findings were published in the Journal of Neuroscience and help us to better understand both the biology of angiogenin and how we can use this to develop future treatments for MND.

In essence, the research group outlined the following pathway for how angiogenin works and how it can go wrong:

When motor neurones are in trouble, they send out angiogenin as their ‘999’ call. This ‘call’ is received by our support cells – the neighbouring astrocytes (so called because they are star shaped).

As angiogenin whizzes it’s way between the outside of the motor neurone and the astrocyte, it needs to find a particular ‘door’ to enter. Cells are quite particular as to what they let inside, so no ‘Joe Bloggs’ can simply walk into a cell unless it has permission to pass (the exception being if it’s something really small!).

As angiogenin plays an emergency service role, it has a pass to be led into the astrocyte. Through this study, the research group were able to specify exactly which ‘gatekeepers’ and doors are used by angiogenin to enter the astrocyte.

Once inside the astrocyte, angiogenin goes into the control centre of the cell – the nucleus. Here, it rolls up its sleeves and starts editing copies of (supposedly, emergency service) genes to help the astrocyte to create more supportive proteins. We don’t yet know what these genes are, but it was declared as a next step for the project in the published paper.

In MND cells with mistakes in the angiogenin gene, it’s function as an editor of gene copies doesn’t happen. Angiogenin is still created in the motor neurone, and passes through into the astrocyte, but it’s supportive function isn’t happening.

This study therefore raises the possibility that angiogenin could be developed and tested further as a possible future treatment for MND to help this supportive function continue.

Testing angiogenin in mice

The second angiogenin story relates to a presentation that was given at the recent European Network for the Cure of ALS (ENCALS) meeting in Dublin by Prof Prehn’s group.

As a follow on to their previous work, Prof Prehn’s research group tested the effectiveness of angiogenin as a treatment for MND in mice. These are called pre-clinical studies, and are essential to provide enough evidence to move to human clinical trials.

In a similar move to our Cogane study, the group have identified through a rigorous MND mouse study that angiogenin could be a promising treatment. Overall, they concluded that it prolongs life by 10 days in mice (which is more effective than riluzole), increased the survival rates of motor neurones, and delayed the progression of symptoms when given after symptom onset.

This study will need to be published and verified in another model, or by another lab following preclinical guidelines to ensure that these results are reliable. After that, the next steps would be for human clinical trials to be initiated. This means that angiogenin could start to be tested in humans in the next few years.

In summary…

Together, these studies prove the value in better understanding the causes of MND, even when the genetic mistake may only cause the disease for a small number of families.

Being able to move a biological finding from the laboratory toward the clinic is always encouraging news.

All in all, it’s great news for the first day of our month of optimism!