Understanding TDP-43 mutations
Dr Ravindra Prajapati, Dr Jemeen Sreedharan, Professor Rosana Collepardo Guevara, Dr Aleks Reinhardt, Dr Claire Troakes and Professor Angus Lamond, King’s College London, The University of Cambridge and The University of Dundee
Discovery Network
Validate therapeutic targets
April 2025 - May 2028
£999,907.93
Summary
TDP-43 is a protein that plays an important role in the assembly line that converts information stored in our DNA into molecules called RNA, which are used as the template for making the proteins within our cells. TDP-43 is known to be dysregulated in about 97% of people living with MND. We also know of over 70 mutations in TDP-43 itself that can directly cause MND, yet few of them have been studied in detail.
The team will study over 70 MND-linked TDP-43 mutants. Using a unique platform of human motor neurons they have developed from stem cells, they will swap out pieces of the TDP-43 gene to systematically investigate each of these known mutations. These iPSCs will be turned into motor neurons and compared to motor neurons with normal TDP-43. The team will use a combination of these cellular models with computational tools and brain tissues kindly donated by people who died from MND, with mutations in TDP-43. This will generate datasets rich with information on the genetics, structure, and function of this protein which is central to the disease.
Why this research is important
By creating this “roadmap of TDP-43 mutations”, the team will provide important insights into what goes wrong in the motor neurons of people living with MND and how to address it. Each variant studied has the potential to refine the design of therapies developed to target TDP-43 dysfunction and inform which specific regions of this gene and the protein it encodes are involved in MND. Additionally, the cell and computer models generated by the team will be powerful tools for the wider MND research community.
To learn more about TDP-43 take a look at our TDP-43 infographic.
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