Understanding how a toxic protein spreads between cells in frontotemporal dementia

Lead applicant: Dr David Hicks

Institution: University of Manchester

Project type: Junior Fellowship

Duration: 36 months

Amount: £218,509

Scientific title: TDP-43: intercellular spread, cellular toxicity and protein-protein interactions in dementia

Why did we fund this project?

Comments from members of the Research Network:

'This sounds a potentially extremely valuable piece of research, both because of its relevance to AD but also to motor-neurone disease'

'The applicant is well qualified for the work. The research is encouraging in that it promises links between FTD, MMD and AD'

'Dr Hicks appears to be an excellent and committed applicant with a worthwhile project, not least because of its implications for younger people'

What do we already know?

Frontotemporal dementia affects the areas of the brain that control aspects such as language, personality and behaviour, called the frontal and temporal lobes. Research shows that some people may have symptoms of both frontotemporal dementia and motor neurone disease (also known as amyotrophic lateral sclerosis or ALS). Motor neurone disease affects the spinal cord and nerve cells that control muscle function, leading to difficulties with movement that can eventually result in paralysis. 

Both frontotemporal dementia and motor neurone disease are characterised by the presence of abnormal clumps of a protein called TDP-43. This protein affects different parts of the brain in the two conditions, leading to the different symptoms. The exact reasons why TDP-43 forms these clumps and how these relate to the underlying causes of the conditions are so far unclear; however researchers believe that TDP-43 cannot perform essential functions when it is in this clumped form. There is also evidence that TDP-43 can spread between nerve cells and cause the TDP-43 present in these healthy neighbouring cells to form the harmful clumps.

What does this project involve?

This project will investigate the mechanisms by which TDP-43 spreads between cells in frontotemporal dementia and motor neuron disease. The researchers will use human nerve cells grown in the lab to find out whether TDP-43 is spread via little packets called exosomes that carry information and proteins between neighbouring cells. They will then find out whether adding these packets of TDP-43 clumps to healthy nerve cells will cause clumping of the protein in these cells as well. They will then investigate the mechanisms by which TDP-43 leaves and enters cells at the molecular level.

How will this benefit people with dementia?

There are currently no treatments for either frontotemporal dementia or motor neurone disease. If the method by which the toxic TDP-43 protein clumps spread between nerve cells is uncovered, this discovery could potentially be used to design potential treatments that target this mechanism.