Finding the key to why TDP-43 accumulates in MND

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A study, part funded by the MND Association and led by Prof Chris Shaw from King’s College London has been published in the June edition of the scientific journal Brain. As we part-funded this study, Prof Shaw sent us the resulting paper from his research yesterday. So, this morning after reading the paper, we thought we’d share with you what they were looking to answer and what they found!

First, a bit of background: One thing that we’ve known for a long time about MND is that by looking through a microscope at an affected motor neurone, brown blobs of proteins that stick together can be seen. It wasn’t until a few years ago that we finally identified a component of the blobs as a protein called TDP-43 that accumulates in around 90% of cases of MND. In 2008, a fundamental breakthrough occurred in that the second causative genetic mistake was discovered in a gene which codes for TDP-43. This was found to be responsible for the cause of between 4-5% of cases of the inherited form of MND and forged a new understanding that the brown blobs containing TDP-43 may have something do to with the cause of MND as opposed to a possible ‘side effect’ of the disease.

TDP-43 is also now recognised to be a cause of a related disease called fronto-temporal dementia (often called FTD). So, by learning more about TDP-43 we can try to identify how it can go wrong in cells to cause both of these diseases.

One mechanism that has been proposed to trigger the accumulation of TDP-43 which may lead to the cause of MND is a defective transport system of the protein into the nucleus – the control centre of the cell. Without TDP-43 having the right ‘key’ to get into the nucleus, it is left to accumulate outside outside of the nucleus. This can have a negative impact on the neurone as TDP-43 cannot perform its regular function and it can cause ‘pile-ups’ within the neurone. What we don’t understand, is what makes TDP-43 not find the right ‘key’ to enter the nucleus. This is the question that this research group set to answer.

What did the research group find?
The research group first silenced (quite literally stopping the function) 82 proteins that are known to be involved with the transport of cargo, such as TDP-43 into the nucleus. From this they identified five proteins that when silenced result in an accumulation of TDP-43 outside of the nucleus. However, three of these are known to be involved in the general transport of all proteins into the nucleus and so were discarded from the study. To make sure the results were not a fluke they repeated their experiments in a total of three cellular models originating from humans and mice. The two proteins that were found to cause an accumulation of TDP-43 outside of the nucleus are called CAS (which stands for Cellular Apoptosis Susceptibility) and Karopherin-β1.

They then went on to see whether the levels of these two proteins are altered in people who have sporadic ALS (the most common form of MND) with TDP-43 clumps (so called TDP-43 positive) or TDP-43 positive FTD. They used brain and spinal cords that had been kindly donated for use in research from people with FTD, people with ALS and healthy controls.

From this, they found that the protein CAS is found in lesser quantities than normal for people who have FTD but did find any differences in samples from people with ALS. Neither FTD nor ALS samples had any significant difference in the level of Karopherin-β1 as compared to the healthy controls.

This means that CAS may play a causative role in FTD but not in ALS. For ALS, this suggests that something else may be going wrong to cause TDP-43 to accumulate outside of the nucleus.

What does this mean for the future of MND research?
From this research project, we now know that although the lack of CAS protein can lead to TDP-43 accumulation in a cell, this is not what causes the accumulation of TDP-43 in MND but may cause the accumulation in FTD. Learning more about how TDP-43 works is important in order for us to understand what the consequences may be if it goes wrong. This research project is a good stepping stone in learning more about TDP-43 and the causes of MND.

The search will now continue to find out what causes TDP-43 to go wrong in MND which may lead to the discovery of a new target for treatments.

We’re currently funding a number of studies relating to TDP-43 to learn more about what it does and how it may cause MND – visit our causes research projects we fund and look out for TDP-43 in the titles!

Link to abstract for scientific paper published in Brain.