Developing a drug screen using nerve cells from a mouse model of MND

In a previous research project funded by the MND Association, Prof Kevin Talbot and colleagues from the University of Oxford developed a new TDP-43 mouse model of MND. Compared to other mouse models of MND, this one accurately reflects the symptoms of the disease and levels of the TDP-43 protein as seen in humans.

TDP43 location in the cell

Location of TDP-43 protein (shown in red) in healthy nerve cells, and how it moves into different parts of the cell in MND

This model of MND also shows how the TDP-43 protein becomes displaced from the nucleus (command centre of the cell) out into the cell cytoplasm, which makes up the cell body. Once TDP-43 has moved to the cytoplasm it is very difficult to shift, as it forms protein aggregates or clumps. It is thought that these clumps contribute to motor neurone cell death.

Prof Talbot’s latest project, together with researcher Dr David Gordon, is using cultured nerve cells from this new mouse model to screen a large library of drugs (our project reference: 831-791).

In the next two years, they will create an automated computerised imaging system that can detect the TDP-43 protein within the nerve cells (and see if it has moved out of the nucleus). With this imaging software the researchers aim to screen thousands of drug compounds in a short space of time, including some which have been approved for other illnesses. A ‘good’ drug will make TDP-43 stay in the correct location within the nerve cell’s nucleus.

This approach will identify any promising drugs quickly, which can then be tested in the new TDP-43 mouse model and human nerve cells (created from induced pluripotent stem cells or iPSCs).

This project is an example of the reducing the number of animals used in research, in line with the 3R’s principle of animal research. Prior to the creation of this model, many mice would have been needed to test the thousands of drug compounds. The Talbot group’s new mouse model means that nerve cells from mice can be used to test the compounds, meaning fewer mice need to be used in total.

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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