Better understanding the role of a protein linked to frontotemporal dementia

Lead Investigator: Dr Ryan West
Institution: University of Manchester
Grant type: Junior Fellowship
Duration: 36 months
Amount: £208,305

Scientific Title: Does Accumulation of POSH Mediate Aberrant Immune and Apoptotic Signalling Cascades Leading to Neuronal Dysfunction in Frontotemporal Dementia? 

Why did we fund this project?

Comments from members of our Research Network:

“Whilst this is aimed primarily at Frontotemporal dementia, it looks like it could add some considerable value to all dementia and seems to be a different approach to the regular avenues of research and so that could be very exciting.”

“While a long way from producing a therapeutic drug treatment for FTD, this research using fruit flies is novel and promising.”

“Well worth investigating further.”

What do we already know?

Frontotemporal dementia is a rarer form of dementia that often affects people under the age of 65. About 40 per cent of people who develop frontotemporal dementia have a family history and several genes have been linked to the condition. There are several different types of the condition, including behavioural variant frontotemporal dementia and progressive non-fluent aphasia.  However, it is not clear what exact biological processes underpin the development of frontotemporal dementia. Very few of the known processes are found in every type of the condition. 

Previous work by Dr West has found that a protein known as POSH accumulates in the brain in several different forms of frontotemporal dementia. Dr West used fruit flies with genetic changes similar to those linked to frontotemporal dementia to understand more about the role of this protein.

Reducing the amount of POSH that the flies had was able to remove some of the symptoms associated with frontotemporal dementia, such as a change in the shape of nerve cells. 

The symptoms of dementia are caused by the death of brain cells. Research also points to a crucial role for the immune system in the development of dementia. POSH is believed to have roles in both cell death and the immune system and Dr West believes that POSH may link these two key processes together in the development of frontotemporal dementia. 

What does this project involve?

Dr West aims to understand more about the role that the protein POSH has during the development of frontotemporal dementia. He will understand how POSH interacts with other proteins in the body and how this could affect their function. He will also use fruit flies to understand more about the role that POSH has, and the effect that the abnormal build-ups of POSH has on nerve cells. He will focus mainly on its effects on cell death and the immune system. He will then understand whether preventing POSH from forming toxic build-ups could rescue some of the symptoms associated with the condition. 

Finally, Dr West will understand whether his findings in flies are the same in people by studying the protein taken from donated brain tissue.  

How will this benefit people with dementia?

There are currently no treatments available for frontotemporal dementia, and very little is understood about the underlying biological causes of the condition. This project will offer a detailed and comprehensive look at one potential mechanism of disease development. This knowledge will help researchers to know whether the protein POSH would be a suitable target for future treatments.