How Neurons Deal with Waste: Implications for Dementia Research

Project summary.
The recent completion of genome-wide association studies and proteomics studies suggests that protein ubiquitylation plays a key role in aging-related dementia including Alzheimer’s disease (AD). In support of this, a mutant form of ubiquitin, UBB+1, accumulates in the brain of individuals with tauopathies including AD. Although UBB+1 cannot be used like wild type ubiquitin to covalently modify proteins, it can still be ubiquitylated and targeted for proteasomal degradation by the Ubiquitin-Proteasome System. However, it has been suggested that polyubiquitylated UBB+1, which accumulates in the aging brain, interferes with normal proteasomal function. This leads to a build-up of misfolded and/or dysfunctional proteins, modulates proinflammatory signal cascades and ultimately triggers neuronal cell death. Despite mounting evidence supporting a role for UBB+1 in the pathogenesis of Alzheimer’s’ disease, the molecular mechanisms underlying UBB+1 regulation and its degradation by the proteasome is poorly understood. This project will provide critical new insight into the events underlying loss of neuronal proteostasis and in doing so may shed light on mechanisms which could be exploited to maintain and/or reactivate proteasomal degradation in Alzheimer’s’ disease.
Applicants should have (or expect to obtain) a First class or 2.1 honours degree (or equivalent) in Biochemistry or Cellular and Molecular Biology. Laboratory experience including undergraduate placement or a postgraduate MRes degree in Neuroscience would be highly desirable.

Research environment.
This project will bring together expertise in ubiquitin signalling (Licchesi’s lab: http://people.bath.ac.uk/jdfl20/JulienLicchesi/Home.html) and neuroscience (Williams’ lab) and therefore provides a unique opportunity for a highly motivated individual to be involved in dementia research. The project will use a pluridisciplinary approach including mouse-derived neurons and neuronal stem/progenitor cells, microscopy and live cell imaging as well as biochemical assays. The project will benefit from the strong portfolio of neuroscience and dementia research at Bath University and the student will receive diverse training and experience through interaction with other groups within our department including the labs of Wonnacott (nicotinic receptors); Brown (protein aggregation); Van den Elsen (biomarkers for AD). The Neuroscience Network at Bath University fosters collaboration and provides links with clinicians at The Research Institute for the Care of Older People (RICE), Brain for Dementia Research-London and the South West Dementia Brain Bank. The University of Bath is also part of the Bristol and Bath Alzheimer’s Research UK Network.

Education & Training environment.
All PhD students join a professional society and attend national and/or international meetings for which some additional financial support is available. University policy is to support postgraduate students in creating their own Personal Development Plan covering all aspects of career management through the PGSkills programme. It comprises a wide range of both on-line and tutor-led researcher development workshops delivered by specialists sourced from within or outside the University and is intended to supplement the research-specific training and skills development available within the research group or department.