Investigating the role of the cell’s waste disposal systems in TDP-linked MND

In April 2016, Dr Jackie Mitchell gave a talk at the Regional Conference in Gatwick to explain the aims of her three year MND Association funded research project. We have now received her second year report. In this blog we explain a little bit more about what she’s been doing. She has already made some good progress.

A little bit of background
One known genetic cause of MND is a defect in the TARDBP gene, which makes the protein TDP-43, that can be found in the nucleus of a healthy cell. The nucleus is the part of the cell that contains all our DNA. Healthy cells also have two major ‘waste disposal systems’ which break down and remove unwanted proteins from cells. More information on the role of TDP-43 in MND can be found on our blog.

In people with TDP-43 linked MND, sticky clumps of TDP-43 form outside of the nucleus. One explanation for why this happens is that the waste disposal systems have failed to remove them. Dr Mitchell’s project aims to understand if these are failing in MND and identify new treatments to stop this happening.

Using mice to further our understanding of MND
One of the ways we can further our understanding of what goes wrong in MND is to model, or replicate, these inherited forms of the disease in animals. The complexity of MND means that much research is required to develop a safe and effective treatment. Wherever possible, this is carried out without animals being used. In some cases, however, where there are no alternatives available, this research will use animals. In these instances, the research is conducted using the guiding principles of the ‘3Rs’:

3rsinfo

More information about the 3Rs can be found on the website of the National Council for the Replacement, Refinement and Reduction of Animals in Research, who are dedicated to ensuring the 3Rs are adhered to in research and testing.

As well as the 3Rs, the welfare of the animals is a primary concern. This is written into law and, in the UK, is enforced by the Home Office.

For more information on funding research involving animals please see our website.

Studying TDP-43 in the spinal cord
In order to be able to see differences between healthy and diseased tissue, Dr Mitchell has developed a model of this TDP-43 linked disease in mice. These mice, known as transgenic mice, develop symptoms similar to those seen in human patients with MND, showing changes in the brain and spinal cord, including appearance of abnormal build-up of TDP-43 in motor neurones.

In an unusual step, Dr Mitchell is using organotypic spinal cord slice cultures from TDP-43 transgenic mice. Organotypic tissue is tissue that is removed from an organ but continues to develop as it would in that organ. These are being used to explore the role of the waste disposal systems in TDP-43 linked MND.

The spinal cord from one mouse can yield up to 30 slices so this method falls neatly into the ethos of the 3Rs – while the use of animals is necessary, the least number of mice possible are used.

keyThe science bit … just follow the trail
Follow the trail to find out what’s happened so far, what will happen next, why it happens that way and what the ultimate goal is.

flow

A foundation for new treatment?
In the majority of cases, TDP-43 plays a major role in the development of MND. Because of the limitations of working with human tissue, using multiple slice cultures from one animal is an excellent way to explore the role of TDP-43 in MND and how it affects progression at different stages, while still showing consideration of the 3Rs. The drugs which most successfully improve disease progression in the spinal cord slices will then be given to adult TDP-43 transgenic mice, to see if the reduction in progression leads to improvement of symptoms. If this is the case, this could be used as a foundation for new treatment therapies against MND.

MND Association position statement on research involving animals
There is an urgent need for ongoing research if we are to stop motor neurone disease killing six people every day. We believe the use of animals in research is essential to understanding, preventing and ultimately finding a cure for MND. We only fund and support research involving animals when no alternatives are available, and where institutions can clearly demonstrate they comply with the rigorous laws that safeguard the welfare of animals used in research in the UK and across the EU. As with all research we fund, there must a clear potential benefit to people with MND.

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