How does the loss of protein building blocks link to FTD?

Lead Investigator: Dr Ryan West

Institution: University of Sheffield

Grant type: Project Grant

Start date: February 2024

Duration: 3 years 

Amount: £354,239.80

Project summary

Dr Ryan West’s research aims to understand how accumulation of toxic proteins leads to frontotemporal dementia, and whether altering specific molecules that form proteins can reduce or prevent nerve cells from dying. 

Project background

Frontotemporal dementia (FTD) is one of the less common types of dementia, and it is mostly diagnosed between the ages of 45 and 65.

The most common genetic cause of FTD is a mutation in a gene called C9orf72. This mutation results in the buildup of 5 toxic proteins, called dipeptide-repeats (DPRs), in the nervous system of people living with FTD. However, how DPRs cause the damage to the brain in FTD remains unclear.

In their previous research, Dr West and his team developed the first, and currently only, animal model of FTD using fruit flies. These fruit flies mimic the brains of people with FTD, causing the build-up of toxic DPRs caused by the C9orf72-mutation.

Using these models, the researchers found that the most toxic of the 5 DPRs activates “stress response” pathways associated with the loss of amino acids in nerve cells. Amino acids are small molecules which join together to build proteins. There are different types of amino acids, some can be made by our bodies (non-essential amino acids), whilst others must be introduced as part of a healthy diet (essential amino acids).

The researchers also found that introducing specific amino acids into the diet can reduce brain damage in flies, and that genetically “turning off” these stress response pathways can further reduce brain damage.

Dr West will investigate these processes further to look at whether production of toxic DPRs results in reduction of essential amino acids, and whether this causes the damage to the brain seen in FTD.

What does this project involve?

Using an elegant model of fruit flies to mimic the human FTD brain, Dr West and his team will find out whether the production of toxic DPRs can cause a reduction of amino acids in the brain, which in turn prevents them from functioning normally. The results will tell us whether this is one of the disease mechanisms in FTD.

Dr West will also investigate whether supplementing the diet of flies with amino acids could help to restore the health and function of brain cells. By modifying specific genes in fruit flies, the researchers could also manipulate the mechanisms by which cells transport these amino acids into the brain, which could help with making the brain cells healthier.

To make sure the same processes happen in the human brain, Dr West will use a more costly model of human brain cells, derived from the skin of donors with and without C9orf72 mutations.

How will this project help people with dementia?

This project will help us understand the damaging processes occurring in the brains of people living with FTD, and what mechanisms we could target in the future to prevent some of this damage.

By looking at the role of specific amino acids, this research could also shed light on whether changes to our diet could be a possible treatment option for C9orf72-related FTD.