Investigating cell waste removal genes in frontotemporal dementia

Research project: Genetic and functional dissection of molecular underpinnings of Frontotemporal Dementia

Lead Investigator: Professor John Hardy

  • Institution: University College London
  • Grant type: PhD Studentship
  • Duration: 36 months
  • Amount: £90,936

Why did we fund this research?

Comments from our Research Network volunteers:

These are the type of fundamental biological questions that need to be asked if we are to determine the underlying mechanisms that drive frontotemporal dementia

Project summary

Frontotemporal dementia is a rarer form of dementia that usually affects people under the age of 65. Some frontotemporal dementia cases have a known genetic link, but exactly how the genetic risk translates to the death of nerve cells is unclear.

In this project, the researchers will analyse the DNA of 6,000 people with frontotemporal dementia to identify alterations in genes responsible for removing waste from cells  and identify the role these genes play in brain cells. If successful, this project could improve our understanding of the processes that are disrupted during the development of dementia and provide new targets for future therapies.

The background

Frontotemporal dementia is a rarer form of dementia that usually affects people under the age of 65. Like most forms of dementia, frontotemporal dementia involves the toxic build-up of proteins, which is thought to lead to the death of nerve cells in the frontal and temporal lobes of the brain. In healthy people, brain cells are able to remove these proteins through processes such as autophagy.

However, there is some evidence that autophagy doesn't work properly in people with dementia. This leads to toxic protein build-up, cell death and ultimately problems with language and change to behaviour

Frontotemporal dementia is much more likely to run in families than the more common forms of dementia. Research have identified changes to DNA in about 30 per cent of people with frontotemporal dementia, but we don’t yet fully understand how these changes to genes lead to nerve cell damage and dementia symptoms. 

Researchers have found that some of these genes are involved in regulating autophagy and other waste removal processes, which might explain why people with frontotemporal dementia can’t clear toxic protein build-up from their brains. 

What does this project involve?

This research group has collected DNA from 6,000 people with frontotemporal dementia – the biggest frontotemporal dementia dataset in the world. In this study, the team will analyse this DNA to look for differences in genes involved in the removal of waste from cells. 

The researchers will then take the most important genes they have identified and use brain cells grown in the lab to test what happens when the activity of these genes is turned down. This should provide the team with some insight into the role of these genes is in the brain of people with frontotemporal dementia. 

How will this project help people with dementia?

There are currently no treatments available for frontotemporal dementia and the underlying cause remains unclear. This project will shed light on some of the processes thought to cause the condition to develop.
 
If we can understand more about how and why the waste removal system plays in dementia we could use this information to improve diagnosis and  provide new drug targets for future treatments. 

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