3.5 Year MRC PhD Programme: Elaboration of small molecule activators of PINK1 kinase and Parkin E3 ligase for improved therapies in Parkinson’s disease

Parkinson’s disease (PD) is a disabling disorder of movement that is currently incurable. Advances in genetics have identified multiple disease-associated genes in which mutations are sufficient to cause Parkinson’s in man. Understanding the function of these genes is likely to lead to new ideas to better treat the disease in the future. Loss of function mutations in the PINK1 kinase and Parkin E3 ligase represent the commonest genetic cause of early-onset Parkinson’s. Recent analysis from our laboratory have demonstrated that PINK1 is activated by mitochondrial depolarization whereupon it phosphorylates two key substrates, the ubiquitin ligase Parkin and ubiquitin [1]. Phosphorylated ubiquitin binds with high affinity to a pocket within Parkin to allosterically induce its activation [2] and this leads to maximal ubiquitylation of substrates at damaged mitochondria to signal their removal by autophagy. More recently we have found that PINK1 activation induces the phosphorylation of a subset of Rab GTPases that have potential as novel biomarkers of PINK1 activity [3]. Our findings indicate that the development of small molecule activators of PINK1 or Parkin would have therapeutic benefit in Parkinson’s. The project will utilize multi-disciplinary approaches using state-of-the-art biochemical and proteomic technologies combined with tissue culture and primary cell work to elaborate robust assays for monitoring PINK1 and Parkin activity in a variety of in vitro and cell-based systems. A variety of screens will be designed and deployed to search for and validate small molecule activators of PINK1 and Parkin. Biophysical analysis will be undertaken to uncover the mode of binding of activators on PINK1 and Parkin combined with crystal structure data where available. The project should reveal new knowledge on how PINK1 and Parkin are regulated and provide a framework for development of pre-clinical compounds for the treatment of Parkinson’s.

The University of Dundee is delighted to be recruiting for five PhD studentships, funded for 3.5 years, to start in September 2017. These projects bring together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. The outstanding biomedical research at the University of Dundee was recognised by its high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.

Eligibility: Applications for these MRC studentships are invited from excellent UK* students expected to hold (or be about to achieve) at least a 2:1 Honours degree in a relevant subject.
*Some EU students may be eligible for a full award if you meet Research Council residency criteria and other exceptions may apply.