Understanding the genetics and biology of Fronto-temporal dementia

Lead Investigator: Dr Sean Sweeney
Institute: University of York
Grant Type: PhD studentship
Amount: £75,000
Start date: October 2010
Completion date: September 2013

Scientific Title: The role of Rab8 and Toll signalling in Fronto-Temporal Dementia related neurodegeneration

What was the project, and what did the researchers do?

Prior to this PhD project, Dr Sean Sweeney's research team had created a fruit fly model of frontotemporal dementia by making the flies produce a defective form of a protein called CHMP2B. They used this model to identify other proteins that may interact with CHMP2B and also play a role in the development of frontotemporal dementia. As part of this, another protein called RAB8 was identified.

CHMP2B is involved in moving membranes (protective layers of material) around cells. RAB8 is also important in doing this and so the researchers hypothesised that the two proteins work together in the same process.

During this project, the researchers obtained fruit flies that do not have the RAB8 protein to further investigate its role. 

What were the key results, and how will this help in the fight against dementia?

They found that these flies have characteristics of neurodegeneration – the connection between their neurones and muscle are overgrown and they die early with very defective behaviour. The researchers investigated the mechanisms that may cause RAB8 deficiency to result in the overgrowth of these connections.

Neuronal connection growth is controlled by two chemical signals, which signal for the connections to keep growing and are degraded when the growth should stop. The researchers found that in the fly models without RAB8, these chemical signals are not being degraded as quickly as they should and so the connections overgrow. The researchers think this may be occurring in neurones affected by frontotemporal dementia.

The neuronal connections with muscle are also overgrown in the researchers' original fruit fly model of frontotemporal dementia, which produces a defective version of the protein CHMP2B. They found that if too much RAB8 was made in these flies, the growth of connections was made normal again. This means that RAB8 may play a role in regulating the normal growth of neurones affected by frontotemporal dementia and in slowing their degeneration.

The research identified other proteins that work to prevent or slow the degeneration in neurones affected by frontotemporal dementia in their fruit fly model. These proteins will be the focus of future work.

What happened next? Future work and additional grants

Other grant applications to continue this work have been submitted, including applications to Alzheimer's Society.

In 2014, Ryan West (the PhD student) will travel to the lab of Prof Fen-Biao Gao in the Department of Neurology, University of Massachusetts Medical School Worcester to work for 4 months. This work will test transgenic mice carrying the CHMP2Bin5 mutation for the signalling events that we see in the fly model. 

How were people told about the results? Conferences and publications

Publications

West, R.J. and Sweeney, S.T. (2012) Oxidative stress and autophagy: mediators of synapse growth? Autophagy, 8(2)284-5

Lu, Y., Zhang, Z., Sweeney, S.T. and Gao, F.B. Syntaxin 12/13, a genetic modifier of frontotemporal dementia-associated ESCRT dysfunction, is required for autophagosome maturation. Molecular Cell In Press (Alzheimer's Society acknowledged for supporting work in the Sweeney lab).

West, R.J., Lu, Y. Gao, F.B. and Sweeney, S.T. Rab8 regulates synapse growth by curtailing Fos/JNK and TGF-ß signaling in the sorting endosome. In preparation.

Conferences and other dissemination activities

Dr Sweeney gave talks on this work at the University of Oxford (May 2013), University of Cambridge (July 2013), the Institute of Neurology, University College London (September 2013) and a conference on Autophagy at the O2 arena, October 2013. In November of 2011 Dr Sweeney spoke on the local BBC radio about our findings and recent publication on aging neurons. Dr Sweeney also runs practical classes for sixth-form students three or four times a year based on our work on neurodegeneration. This practical was also run for 20 University of York Alumni over the University 50th Anniversary Alumni Weekend.

Mr West presented posters on his work at Workshop on membrane regulation at the synapse, Baeza, Andalucia, Spain, October 2013, at the Society for Neuroscience Satellite Meeting on Neurodegeneration, November 2013, the Drosophila Neurobiology meeting in Padua, Italy, 2012 and Manchester 2010. Mr West spoke at the Northern Area Lay Members meeting in June 2012, a talk that was greeted very warmly. We made the presentation available to attendees on request, eventually resulting in 24 requests. A second BBSRC funded PhD student from the Sweeney lab will be undertaking a 3 month internship in the York Alzheimer's Society Office to further his understanding of the issues of dementia to Society. Ryan also won the prize for best speaker at the Department of Biology, University of York, final year PhD talks, one of three first prizes out of 40 contestants. He also won second prize for his talk at the North of England Cell Biology Meeting in Sheffield in September 2013 and 1st prize for the York Cell Biology Synposium.

Both Dr Sweeney and Mr West were interviewed for an article for the Yorkshire Post (front page, 2nd November 2013) as part of the Alzheimer's Society funding drive for Christmas 2013. The interview resulted in a written article and online videos of the interview.