4 Year Wellcome Trust PhD Programme: Mapping signal transduction pathways in Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder yet there are no drugs that can slow or cure the disease. The discovery of genetic mutations in rare familial forms has transformed our understanding of the origins of PD but the function of these genes is poorly understood. Mutations in PTEN-induced kinase 1 (PINK1) cause autosomal recessive PD. Over the last few years our lab has made a number of groundbreaking discoveries relating to PINK1 function that have elaborated a novel signalling pathway including the discovery that PINK1 can phosphorylate ubiquitin at residue Serine65 to activate a E3 ligase named Parkin. In ongoing studies we are investigating the key regulators of PINK1 and Parkin function using state-of-the-art mass spectrometry technologies combined with Cas9/CRISPR technologies to genetically knockout genes in somatic cell lines. We are also investigating the molecular mechanism of how PINK1 is activated. We have recently generated highly sensitive PINK1 monoclonal antibodies and wish to utilize these together with mass spectrometry methodologies to determine physiological binding partners of endogenous PINK1. Our lab also studies signalling in PD relevant cells including primary mouse dopamine neuron cultures.