Understanding and preventing the protein build-up that can cause nerve cells to die

Prior research has already shown that build-up of the protein TDP-43 is found in the majority of cases of MND (irrespective of whether it was caused by an inherited genetic mistake). In healthy nerve cells, TDP-43 is normally found in the cell nucleus (the management centre of the cell). But when we look at nerve cells from people with MND, we see that the TDP-43 has left the nucleus and moved to the main body of the cell and clumped together. We do not know why this happens, or how it leads to cell damage in MND.

In nerve cells, old proteins are ‘tagged’ for breaking down and disposal (or recycling). We have an idea that TDP-43 may impact on this process.

To investigate how TDP-43 causes motor neurones to die, Dr Jacqueline Mitchell and her team at King’s College, London have created several new mouse models to investigate how TDP-43 causes motor neurones to die in MND (our grant reference: 828-791).

In the first year of this project, Dr Mitchell has established a mouse slice culture model of MND. Slice cultures are very small sections (less than half a millimetre thick) which have been dissected out of the mouse’s spinal cord .These slices are placed in a special dish in ‘six-well plate’, which keeps the slice cultures alive for several months. (The plates are small too, only the size of an A6 piece of paper – A4 folded into four). The complex network of nerve cells within the spinal cord can then be studied to see how they are affected in MND.

Slice cultures diagram

The individual well plate is shown on the right, with the slice cultures circled in yellow. Image courtesy of Dr Mitchell

Being able to study each cell culture for several months reduces the number of mice needed for this type of research, and is an example of the ‘3Rs’ principles of animal research.

In order to work out how TDP-43 may be affecting the cell waste disposal system, Dr Mitchell first needed to see how TDP-43 and other proteins look in cells of healthy mice and those with rapid progressing MND. Clumps of TDP-43 are clearly seen in the nerve cells from the rapid progressing MND mouse model. The next part of her study will investigate how the cell waste disposal system interacts with TDP-43.

Dr Mitchell gave a presentation of her research at our Gatwick regional conference in April. You can watch this online.

For more information on funding research involving animals please see our website: www.mndassociation.org/animalresearch

Throughout June 2016 MND Awareness Month will be highlighting the rapid progression of the disease in its powerful Shortened Stories campaign, sharing the experiences of people currently living with MND, or who have lost loved ones to the disease, through art, poetry and film.

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