How does mutant ubiquitin drive neurodegeneration?

A 3-year PhD position fully funded by Alzheimer’s Research UK is available starting October 2017 in the Ubiquitin and Cell Signalling laboratory of Dr Julien Licchesi (https://julienlicchesi.wordpress.com/) in collaboration with Dr Robert Williams (http://www.bath.ac.uk/bio-sci/contacts/academics/robert_williams) an expert in molecular mechanisms underlying Alzheimer’s Disease, at the University of Bath.

As the number of patients affected by various forms of dementia including Alzheimer’s disease (AD), frontotemporal dementia and dementia with Lewy bodies increases, the number of new experimental dementia drugs in the clinic is at an all-time low with an estimated 99.6% failure rate for AD. There is therefore an urgent need to identify novel molecular mechanisms relevant for the initiation and progression of neurodegeneration, which could be targeted by novel therapeutics. The recent completion of genome-wide association studies together with proteomics studies have confirmed that protein ubiquitination plays a key role in aging-related dementias.

UBB+1 is a mutant form of ubiquitin, which accumulates in the brain of patients with AD. Although UBB+1 cannot be used like normal UBB to covalently modify proteins it can still be polyubiquitinated and targeted for degradation by the Ubiquitin-Proteasome System (UPS). In AD brain, and other tauopathies, the polyubiquitylated form of UBB+1 accumulates and it is this toxic protein pool which acts as a potent inhibitor of the UPS.

The aim of the project is to identify, in neurons, the E3 ubiquitin ligases and deubiquitinases (DUB) which regulate UBB+1 ubiquitination and define the molecular mechanisms linking UBB+1 to UPS inhibition. The appointed student will develop and use a range of cellular approaches, including transfection of neurons with viral vectors, high-content and confocal microscopy, biochemical assays such as in vitro ubiquitination assays and protein-protein interaction studies. The project will benefit from ongoing collaborations with chemical biologists, proteomics experts and scientists from the ARUK Bristol and Bath Network. Basic research discoveries made by the student will be evaluated in post mortem brain samples through collaboration with Brains for Dementia Research in London and the South West Dementia Brain Bank in Bristol

The student will join a multi-disciplinary team working on highly novel questions in the field of dementia research and will have the opportunity to present data at national and international conferences.