Using stem cell technology to understand more about how MND and FTD develop

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The MND Association are funding Prof Kevin Talbot, Dr Ruxandra Dafinca (née Mutihac) and colleagues at the University of Oxford, who are investigating the link between the C9orf72 and TDP-43 genes in MND. We wrote about this research earlier in the year. As we’ve recently received their first year progress report we wanted to give you an update on what they’ve achieved.

Dr Ruxandra Dafinca

Background to the project
A defect in the C9orf72 gene is the biggest genetic cause of the rare, inherited form of both MND and frontotemporal dementia (FTD). In addition, deposits of TDP-43 protein are found in most cases of MND and FTD.

The team had several research questions that they wanted to answer:

  • How does C9orf72 cause damage in MND?
  • How does it cause damage in FTD?
  • Is there an overlap in the way that C9orf72 and TDP-43 cause damage?

To find the answers to these questions, the team are using induced pluripotent stem cell (iPSC) technology.  This technology allows them to take skin cells from people with a specific gene defect and turn them into the neurones affected in MND and FTD, which can be studied in a dish in the lab.

What’s happening inside the C9orf72 neurones?
Motor neurones (the cells that are damaged in MND) can be thought of like terraced houses along a street. In MND, lots of the houses in the street become damaged. To understand what’s really going on in MND, we need to know what’s happening inside the motor neurones – in other words, we need to peer into the houses!

This is exactly what the team did – they looked at what’s happening inside the iPSC derived motor neurones with the C9orf72 defect.

The first thing that they saw was that calcium levels were severely disrupted. Calcium is important for maintaining electrical activity, so this is a bit like having intermittent electrical faults in the houses along the street. Other parts of the motor neurones were also found to be faulty. The team are now investigating whether the following are linked to the disrupted calcium levels:

  • The batteries of the motor neurone cells (the mitochondria) were damaged, which is like the power generator of the houses becoming faulty.
  • There was a lot of stress inside the cells. Stress is like an alarm that signals that something is wrong, like a fridge alarm going off if the fridge is left open for too long.
  • The way that the cell recycles proteins was faulty. Imagine if the rubbish and recycling were never taken out, leading to a build-up of unwanted waste.
  • Some cells were deemed unsafe and marked for destruction – a bit like having some of the houses condemned and demolished!

They also did some tests on the neurones affected in FTD, and saw some similar problems (alarms, faulty cell recycling and cells marked for demolition). This suggests that there might be an overlap in the way that the neurones get damaged in MND and FTD.

Is there an overlap in the way that C9orf72 and TDP-43 cause damage?
The team are now developing neurones with a TDP-43 defect using stem cell technology. They will be grown into the neurones affected in MND and FTD and will undergo similar testing. This will help to establish whether there is an overlap in the way that C9orf72 and TDP-43 cause damage in MND and FTD, which is crucial for designing targeted new therapies.

Find out more
This year, some of the findings from this work have been published in the prestigious journal Stem Cell, which can be accessed here.

This week is Open Access week. Fittingly, this work is open access, which means that it can be freely viewed and shared by anyone. Find out more about open access on our website.

4 thoughts on “Using stem cell technology to understand more about how MND and FTD develop

  1. Really interesting – and a helpful analogy with the terraced houses! Thank you.


    Hilary Fairfield Regional Delivery Manager for the South Motor Neurone Disease Association Tel: 01373826289 Mobile: 07923590899

  2. Thanks another wonderful update. I live in bungalow hope ok for that as well as terraced house. Keep the good work going.

  3. My daughter has been helping with this research, we have this same genetic problem in too many of our family. Please, please keep up this vital work.

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