Investigating differences in protein production in MND

Investigating differences in protein production in MND

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In June we hosted the second MND EnCouRage UK event for early career researchers (ECR’s) which aims to support them to continue working in the field of MND. The event included lots of talks and workshops from senior researchers to provide tips and advice on moving forward in their careers and help them to develop new skills in areas like presenting their work to non-scientific audiences. We also challenged the ECR’s to write a blog to explain their research to the MND community. This guest blog is from Hannah Smith, one of the ECR’s who came to the event this year.

A photo of Hannah at a lecturn at the ECR event

My name is Dr Hannah Smith, and I’m a post-doctoral researcher at the University of Edinburgh. My project is supervised by Professor Tom Gillingwater, and my work is funded by MND Scotland. My current research focuses on comparing healthy motor neurons and those with MND/ALS, specifically focusing on early changes to the cellular machinery and how the motor neurons produce the proteins they need to function. I’ll discuss the specifics of that, and why we are interested in finding out this information, in the next section.

Before my current research project, I completed my PhD in the lab of Professor Catherina Becker, using zebrafish to investigate the development of motor neurons in a model of another type of motor neuron disease, Spinal Muscular Atrophy. After completing my PhD in 2019, I then worked on a post-doctoral project at the National University of Singapore, researching bone development and osteoporosis, in Associate Professor Christoph Winkler’s group.

However, my research passion is truly motor neuron disease, and since 2022 I’ve refocused on this devastating disease and plan to dedicate my career to it. As many of us know, MND is a complex disease, and we still don’t understand the mechanisms of why and how motor neurons degenerate and die off. Answering these fundamental questions on what is happening inside these incredibly specialised cells during MND is thus an important field of research, and it’s what I’m passionate about investigating.

One highly challenging aspect of MND is that we still don’t have a test for it, leading to delays in diagnosis, which is clearly devastating to people living with MND. Another vital issue is that there are still almost no approved treatments for MND. As a scientist, I think that these two issues may have a common solution – we need to identify the differences between healthy and diseased motor neurons, but as early as possible in the disease onset. The earlier we can identify changes in MND cells, the more useful it is both for developing diagnostic tests and for treatment interventions to slow down progression. In my research, I am particularly interested in the proteins inside motor neurons, which are the building blocks of the cells and are constantly produced and then broken down to maintain healthy functions. Previous research has shown that TDP-43, a protein which is very commonly defective in people living with MND, can disrupt the ability of motor neurons to correctly produce other proteins. However, we don’t know exactly which disrupted proteins are contributing to MND progression, which is what my project aims to identify.

A photo of the venue for the conference.

Blog | 10 October 2023 | Research Development Team
Terrific TDP-43 Talks in Trieste

I’m using a cutting-edge technique called Translating Ribosome Affinity Purification, which is conveniently shortened to TRAP. This is also very accurate, as like a fishing net, I use this technique to TRAP the proteins being actively produced inside the motor neurons. This gives me a snapshot of the inner workings of the cell. I’ve done this for both healthy and diseased motor neurons, focused on the earliest stages of disease onset. The data I generate from the TRAP technique is huge, as motor neurons are producing hundreds or thousands of proteins all the time, and then I can compare the healthy and diseased datasets to find changes. Imagine the most complicated game of “Spot the Difference” that you’ve ever seen, and that’s my research data! By very carefully looking for differences between the healthy data and MND data, I’ll be able to identify new possible targets for further research. For example, a protein which is highly produced in the healthy cells but then is missing in the MND cells may be required to maintain healthy motor neurons. If this protein stops being produced early in MND onset, then restoring it via drugs may help protect the motor neurons or slow their degeneration. On the other hand, if we find a protein produced only in the MND cells, that is absent in the healthy cells, it may be toxic and damaging, and therefore contributes to motor neuron degeneration. Such a protein would make an excellent target for drugs to reduce it, slowing down its damaging effect. It could also be used as a basis for a diagnostic test, as its presence is only found in the motor neurons of people with MND.

Currently, I am looking through my gigantic “Spot the Difference” datasets to find these exciting new proteins. Then, I need to validate their mechanisms in the motor neurons, to check that they are really the most interesting and worthy of future research. We will see many, many changed proteins between our two groups, so it’s important that we double-check our findings and prioritise the best ones before moving forward. As a fundamental scientist, I’m working at the very frontier for finding some as-of-yet unexplored pathways for MND. I’m really excited and hopeful to generate new avenues towards treatment development or diagnostics, so please watch this space!

We would like to thank Hannah for taking the time to write this guest blog about her work and also thank everyone involved in making MND EnCouRage UK 2023 such a success.

The MND Association’s vision is a world free from MND. Realising this vision means investing more in research, further developing partnerships with the research community, funding bodies and industry, while ensuring that advances in understanding and treating MND are communicated as quickly and effectively as possible. Our Research Development team, composed of 11 members, work hard to achieve this. Principally, the Research Information team within this are involved in communication activities including this MND Research blog.