The 11th Annual ENCALS meeting highlights how TDP-43 spreads in MND

The European Network for a cure of ALS (ENCALS) held its 11th Annual meeting in Sheffield from 31 May to the 2 June. The weekend was full of glorious British sunshine and more than 200 international scientists and clinicians were also able to enjoy a range of incredibly interesting talks about the latest developments in MND research.

A particular talk caught my attention on the first day by Dr Johannes Brettschneider from the University of Ulm in Germany. Dr Brettschneider explained how his research had shown the stages and spread of the protein TDP-43 in ALS (the commonest form of MND).

Dr Brian Dickie, Director of Research Development, said: “The key to defeating MND lies in fostering strong collaborations between neurologists, healthcare professionals, research scientists, early career investigators and students in the field of MND and the 11th Annual ENCALS meeting in Sheffield provided that opportunity. The MND Association was proud to support this event.”

‘Special’ staining

At the end of an afternoon of talks on the MND- causing genes C9orf72, FUS and SOD1, Dr Brettschneider engrossed over 200 delegates with his talk on the TDP-43 protein and how it spreads in ALS.

Although TDP-43 genetic mistakes are a rare cause of MND, scientists are especially interested in the TDP-43 protein because in the vast majority of cases of MND (irrespective of whether it was caused by an inherited genetic mistake), TDP-43 protein forms pathological clumps inside motor neurons.

The study (which is a collaboration between Dr. John Trojanowski and Dr. Virginia Lee from the Penn University Center of Neurodegenerative Disease Research in Philadelphia, America and the group of Dr. Heiko Braak in Ulm) used a technique known as ‘immunohistochemistry’.  This technique involves taking tissue samples of the brain and spinal cord from people who have died from ALS. The researchers would then make extremely thin slices of the tissue, which could then be stained using a ‘special stain’ and viewed under a microscope.

The stain used by Dr Brettschneider only ‘stained’ the TDP-43 protein in the samples, meaning that he could see the amount of TDP-43 in different areas of the brain and spinal cord.

Using the clinical information and TDP-43 staining this would allow Dr Brettschneider to stage the disease.

Image kindly provided by Dr Robin Highley, SITraN: (top left) a motor neurone with a skein-like neuronal cytoplasmic inclusion, next to a normal motor neurone (bottom left) on TDP-43 immunohistochemistry.
Image kindly provided by Dr Robin Highley, SITraN: (top left) a motor neurone with a skein-like neuronal cytoplasmic inclusion, next to a normal motor neurone (bottom left) on TDP-43 immunohistochemistry.

Axonal ‘telephone wires’ do more than just talking

Dr Brettschneider showed that TDP-43 increased in different areas of the brain and spinal cord during different stages of the disease. Amazingly, he also showed how ALS (characterized by clumps of TDP-43) spreads from one are of the body to another.

A motor neurone consists of three parts; the cell body, axon and nerve ending. The cell body contains the nucleus, or the control centre of the cell. When a message travels from the brain the cell body sends the message down the axon. Like telephone wires, the axon carries the message to the muscle, where the nerve endings cause the muscle to move.

However, in ALS it seems that these ‘telephone wires’ do more than just carry a message. The protein TDP-43 forms ‘clumps’ in the motor neurones and it seems that these clumps use the axon to travel from one motor neurone to the next (possibly explaining why someone get’s weakness in their arm and then their hand).

Another key finding was that TDP-43 clumps develop in the front part of the brain (prefrontal cortex), which is responsible for personality and may explain the development of cognitive symptoms.

Dr Brettschneider explained the importance of this research While spreading of disease-related proteins has been described for other neurodegenerative diseases like Alzheimer’s disease or Parkinson’s disease, this had not been previously shown in ALS. Now, we can show evidence that supports a spreading of the major disease protein TDP-43 in ALS across specific regions of the brain and spinal cord with ongoing disease.

 If these findings can be confirmed (for example in cell culture or mouse model studies) then this could lead to the design of new treatments specifically aiming to impair the spread of TDP-43 protein clumps.

Dr Johannes Brettschneider from the University of Ulm in Germany at ENCALS
Dr Johannes Brettschneider from the University of Ulm in Germany at ENCALS

Furthermore, we believe that our findings offer a better understanding of disease progression in ALS.  Our data implies that TDP-43 spreads throughout the prefrontal cortex with ongoing disease, thereby lending support to the idea that all ALS patients could eventually develop “frontal type” cognitive deficits.”

The future

Dr Brettschneider commented why this research is important to people living with MND explaining that “If these stages can be reproduced in patients with ALS they could offer a new way to assess disease progression and response to new treatments. We hope that our study provides the essential groundwork for strategies designed to prevent pTDP-43 spread.”

This research is only the beginning and more work is needed, Dr Brettschneider also explained what he hoped to do next with these exciting results. “There were restrictions in time and availability of the tissue samples during this study, so we were unable to determine how and where exactly ALS begins in the very early stage of the disease. Therefore, an important next step in our work would be to analyze very early cases with ALS to look at TDP -43 spread as this offers the most promising window for therapeutic intervention.”

Reference

Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 May 20. doi: 10.1002/ana.23937. [Epub ahead of print]

Major new research finding raises some old questions

Hot on the heels of ‘Brain Awareness Week’, comes ‘National Science Week’, with the University of Sheffield enthusiastically organising a numerous activities in their week-long Festival of Science and Engineering, including today’s Open Day at the Sheffield Institute of Translational Neuroscience (SITraN). This event was to include talks by Dr Chris McDermott and Prof Pam Shaw on MND and the role that SITraN plays in the search for effective treatments for neurodegenerative disease.

Unfortunately…… last night’s snow has put the kibosh on that, so instead of heading up the M1 to Sheffield, I decided to use some of the saved time to catch up on some reading – in particular a recent paper that came out in the journal Nature, from an international consortium, led by the scientists from the Austrian Academy of Sciences in Vienna.

The best seven pages in ten years

A senior MND researcher emailed me to say it’s one of the best papers he’s read in the past 10 years and I can understand where he’s coming from. Not only does the research identify a previously unknown cellular process that causes selective motor neuron degeneration, but it also appears to tie together several of the pieces of the pathological jigsaw: disruption of RNA metabolism, oxidative stress and programmed cell death pathways.

As impressive is the sheer amount of work that has gone into this seven-page paper. OK, there are also several extra pages of online supplementary material (one of the great benefits of online publication) but I reckon there is the equivalent of at least three PhD theses and several years of work in there!  

In a nutshell, the researchers created a mouse that has a defect in an enzyme called CLP1 and these mice develop progressive motor neuron degeneration. I’m not going to go into the detail, but rather focus on one interesting item that was buried in the text.

Genetic environment matters for CLP1

When researchers initially tried to create the mice they found that the mice all died well before birth. So they tried using a different strain of mice, but got the same result.

A third strain produced live mice, with normal numbers of motor neurons at birth. However from about the age of four months, these mice then developed a progressive muscle weakness and loss of motor neurons over the course of several months.

The paper focuses in on what’s going on in these mice, but it also raised additional questions for me, such as:

“Why did these mice survive into adulthood, when two other mouse strains didn’t – and is there something different in the genetic make-up of these mice that has basically protected them into adulthood rather than killing them as embryos?”

MND Association funded research on genetic environment

Other groups have noticed that when SOD1 mice are bred on different background strains, it can have a profound effect on disease progression and survival. This brings us nicely back to SITraN, as Prof Shaw and her colleagues are looking at precisely this issue, in an MND Association-funded collaboration with Prof Caterina Bendotti in Milan.

They are looking at the gene expression profiles (basically which genes are switched on and off) in the motor neurons of two strains of SOD1 mice, one of which develops the disease and later age and also lives much longer.  By working out patterns that are linked to specific biological processes, they are starting to pinpoint pathways which are driving the disease and also which ones might be slowing the disease. Some of their findings were presented at the most recent International Symposium (Abstract C61).

If there are protective genes at work in the mice, might the same be happening in humans?

The search for ‘good’ genes hots up

I’m often asked about Steven Hawking – how come he’s lived so long?  For years, one of my pet theories has been that there is something in his genetic make-up that didn’t stop the disease from occurring, but is ‘pushing back’. That’s becoming an increasingly popular and productive area of investigation – as genetic researchers extend their focus from finding ‘bad’ genes that cause or predispose people to develop MND, to potentially ‘good’ genes that might slow down the disease. A couple of candidates have been identified, most notably the EphA4 gene.

The search for these disease-modifying genes needs joined up collaboration between researchers around to world and it’s heartening to see how everyone in the field is starting to get together to pool their samples and data, which will allow the genetic profiles of those with exceptionally slowly progressing MND to be analysed in much larger numbers than ever before. If good genes can be identified and their roles understood, it will open up exciting new treatment opportunities.

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!