Investigating a potential pathway in the development of frontotemporal dementia

Research project: Investigating C9orf72 Protein Ubiquitination, a Possible Drug Target for C9orf72-related Frontotemporal Lobar Degeneration

Lead Investigator: Dr Kurt De Vos
Institution: University of Sheffield
Grant type: PhD studentship
Duration: 36 months
Amount: £84,738

Why did we fund this project?

Comments from members of our Research Network:

"I can see that this research may well have far reaching possibilities and may be very beneficial to people with dementia"

"I work alongside several carers who are looking after people with an FTD diagnosis and see the huge impact this has on their daily lives so to be able to offer the hope of the next step towards treatment is very positive."

"A very interesting project."

What do we already know?

Frontotemporal dementia is a rarer form of dementia that usually affects people under the age of 65. It is caused by the death of brain cells in the frontal and temporal lobes of the brain. 

Most forms of dementia are characterised by the presence of toxic build-ups of proteins. In frontotemporal dementia these include proteins called tau and TDP-43. Build ups of proteins are not unusual and mostly they are removed from the cell by a process known as autophagy. However, there is some evidence that autophagy doesn't work properly in dementia which leads to these toxic proteins building up and damaging brain cells. This could be leading to brain cell death and symptoms of dementia. 

The theory that problems with autophagy could be related to frontotemporal dementia is strengthened by the knowledge that a gene associated with some forms of the condition, called C9orf72, is linked to this process. Previous work by Dr De Vos has indicated that a lack of C9orf72 leads to less autophagy happening in the cell. 

What does this project involve?

The PhD student on this project will investigate whether restoring the autophagy function in cells in people with C9orf72-linked frontotemporal dementia could be a possible treatment for the condition.  

Proteins are often 'tagged' for destruction in the cell by the addition of a protein called ubiquitin. The team will investigate whether preventing the addition of ubiquitin to C9orf72 can stop it from being destroyed and restore the autophagy function in the cell. They will investigate this using nerve cells grown in the lab to understand more about the function of C9orf72 and whether the removing ubiquitin tag can affect the function of the protein and whether this can have an impact on autophagy. 

How will this benefit people with dementia?

There are currently no treatments for frontotemporal dementia. This project will shed light on some of the underlying processes thought to contribute towards the development of the condition. If successful, researchers can then further investigate whether targeting the ubiquitin tag on C9orf72, or boosting autophagy, would be a suitable avenue for potential treatments. 

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