An insight into TDP-43 – An ENCALS 2015 meeting report

Medical Research Council (MRC)/ MND Association Lady Edith Wolfson Clinical Fellow, Dr Jakub Scaber, attended the European Network for a Cure of ALS (ENCALS) meeting from 21-23 May 2015.

Reporting back from the event in Dublin, Dr Scaber summarised the TDP-43 session, including his presentation on recent developments in his own Association-funded research:

The fifth session of the ENCALS meeting focussed on a protein called TDP-43: This is the protein that accumulates in the brains of people living with MND and has been tightly linked to the development of the disease. Abnormal forms of this protein can be found in 98% of cases and this session had some very interesting basic science discoveries around this topic.

I myself (Jakub Scaber) was given the opportunity to present. Using donated brains from patients with the C9orf72 mutation from our Oxford Brain bank, I reaffirmed the importance of the abnormal TDP-43 protein in this mutation. This research showed that TDP-43 changes after death were also seen in the brain and spinal cord areas that were clinically affected in life.

The second speaker, Dr Mario Sabatelli from the Università Cattolica del Sacro Cuore in Rome showed how abnormalities in skin cells taken from people living with MND could be used to study the condition. Skin biopsies take only a few minutes and are a very safe and simple for procedure, and the cells themselves can be grown as skin cells in a dish. Dr Sabatelli proved that these have mild changes of TDP-43 even though they are not neurons, showing the potential usefulness of these cells for very basic biological studies. Because they are much simpler and cheaper to grow than nerve cells and stem cells they may well have their role in MND research.

The third speaker was Eva-Maria Hock from the University of Zurich. She showed a very exciting new technique in which thin slices of mouse brain can be kept alive in a dish for weeks and the response to abnormal protein can be monitored, and indeed was able to show this for TDP-43 abnormalities. The advantage of such a model is that changes to whole networks, like brain tissue, in response to abnormal TDP-43 can be seen in the dish, which was beautifully shown in this presentation.

The fourth speaker was Marisa Feiler from the University of Ulm. She used yet another technique to study TDP-43 abnormalities in a dish. A unique fluorescent version of TDP-43 was designed which only ‘lights up’ when there is abnormal clumping. Using a special chamber to look at the long processes of nerve cells she was able to demonstrate how nerve cells can take up abnormal protein with their long processes and transport them to their core where they can then ‘clump’ and cause trouble.

The final speaker of this session was Professor Francisco Baralle. He had originally discovered the first function of TDP-43 and has since made huge contributions to the field of MND. He gave an exciting overview of the developments of the last 20 years and then proceeded to present the fly model of TDP-43 that he is currently working on. Although flies seem unrelated to us, certain key proteins found in humans are very similar to proteins found in flies. TDP-43 is one of these key proteins – we call it ‘conserved between species’, which implies that it is a very important protein for the function of most organisms. Studying the basic biology of this protein in flies by modifications is much simpler than in humans and can give us important clues, or even allow us to investigate preliminary treatment avenues, as Professor Baralle was able to show.

The session was extremely enriching and promising – a whole range of different disease models was shown, and each provided us with a different aspect on how TDP-43 fits into the whole MND picture. As TDP-43 is found in the majority of cases of MND, ultimately understanding the contribution of this protein to the disease gives us a promise for finding a targeted treatment.

Dr Scaber reported on his research during our ‘Blog a day’ during last year’s MND Awareness month in June. You can read more about his research here and in our newly updated ‘Research we fund’ information sheet.