University of Dundee

4 Year Wellcome Trust PhD Programme: Elucidation of cell signalling pathways in Parkinson’s disease

Parkinson’s disease is a leading cause of neurodegeneration. Despite decades of research, there are still no drugs available that can slow or halt disease progression. The discovery of rare gene mutations in patients with familial Parkinson’s has provided clues to the molecular basis of the disease however, the function of most genes is poorly understood. Our laboratory is interested in how mutations in the PTEN-induced kinase 1 (PINK1) lead to autosomal recessive Parkinson’s. We approach this question by defining the cell signalling pathways controlled by PINK1 and investigating how mutations then disrupt these. We have identified key substrates of PINK1 namely the Parkin E3 ligase and Ubiquitin and together with other labs have linked PINK1 to mitochondrial quality control pathways. However, very little is known on the upstream regulation and activation of PINK1. The project will identify the key binding partners of PINK1 using state-of-the-art mass spectrometry technologies combined with Cas9/CRISPR technologies to genetically knockout genes in somatic cell lines. We have recently generated highly sensitive monoclonal antibodies against the downstream components of PINK1 signalling and this will enable facile validation of functionally relevant partner proteins. We also have collaborations with leading clinical centres in Europe that will allow analysis of the interactors in appropriate Parkinson’s derived cells and tissues including post-mortem brain.