Motor neuron disease (MND) is an incurable paralyzing degenerative disease that affects 1 in 300 people and usually causes death within 3 years of onset. MND overlaps with the brain disease frontotemporal dementia (FTD), the second commonest dementia in the under 65s and another fatal condition that causes behavioural and language dysfunction. Almost all patients with MND and half of those with FTD have an important common feature, which is the clumping and malfunction in the brain of a complex protein called TDP-43. This essential protein has multiple roles in controlling expression of other proteins. We previously discovered that TDP-43 happens to affect the expression of another key brain protein called tau. When TDP-43 levels rise too high it causes an increase in the length of tau messenger molecules, which make tau protein. In theory, this could cause tau protein to end up in the wrong place in nerve cells and disrupt the way that nerves communicate with one another at junctions called synapses. Tau is important because it malfunctions in the commonest cause of dementia, Alzheimer’s disease (AD). In a separate project we also found that TDP-43 can cause nerve cells to die by activating a protein called GSK3, and GSK3 is known to alter the structure of tau. Thus, we had two pieces of evidence strongly linking TDP-43 and tau. We believe that if we can understand the links between TDP-43 and tau there is the possibility we could identify new therapies that could benefit patients with MND, FTD and AD. 

 

PROJECT:

In a study initiated with funding from the Psychiatry Research Trust we have been investigating how TDP-43 disturbs tau length and synapse function using our TDP-43 mouse model of MND-FTD. We have been examining the brains of these mice using cutting-edge microscopic techniques and hope to have results by summer 2025. So far we have confirmed that there are higher levels of longer forms of tau in our mice. The question remains as to whether this longer tau is in the wrong place in neurons and disrupts the synapse. In parallel studies, we have been investigating the link between TDP-43 and GSK3. This work is nearly complete and currently available to read online (https://doi.org/10.1101/2021.02.03.429569). We have examined mouse, rat and human neurons expressing TDP-43 in Petri dishes and found that when we reduce the activity of GSK3 using drugs we can reduce TDP-43 toxicity and improve nerve survival. We believe this survival effect works directly on TDP-43 rather than through tau, because we see that levels of TDP-43 are reduced when we add the drugs. This suggests that GSK3 inhibition has therapeutic potential in MND, FTD and AD. The question remains as to whether these drugs are safe for use in humans and we therefore need to do more research. We are continuing these studies with funding from Alzheimer’s Research UK, the Wellcome Trust and other charities. 

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