George Tofaris

We are studying basic cellular pathways that could inform the development of targeted biological therapies in neurodegenerative and neurogenetic disorders. To this end, we use Drosophila models and iPSc-derived neurons to identify cellular perturbations in response to expression of toxic proteins implicated in neurodegeneration and a range of biochemical assays to understand underlying mechanisms.

Of particular interest to our group is the study of ubiquitin-dependent lysosomal degradation pathways. It is now well established that transport of proteins or organelles to lysosomes and their subsequent degradation is especially relevant to Parkinson’s disease. An important signalling cascade in this pathway is the conjugation of a ubiquitin chain to protein-substrates or organelles such as mitochondria.  This is a three-step catalytic process, involving a ubiquitin activating enzyme E1, a ubiquitin conjugating enzyme E2 and a ubiquitin ligase E3. There are more than 650 E3s, which regulate substrate specificity and different types of ubiquitin chains, which determine the cellular fate of the ubiquitinated substrates.

We first demonstrated that α-synuclein is ubiquitinated in Lewy bodies and subsequently identified Nedd4 as a critical E3 in α-synuclein trafficking and toxicity. More recently we showed that in human brain, the expression of the deubiquitinase Usp8 is increased in dopaminergic neurons with Lewy bodies, opposing α-synuclein clearance and increasing its toxicity in the Drosophila model.  Because the cellular accumulation of α-synuclein is causatively linked to neurodegeneration, our findings suggest novel mechanistic insights into the pathogenesis of Parkinson's and related diseases, which are the focus of current studies.

We are also interested in the role of mitochondrial dysfunction in  hereditary forms of neurodegeneration and the study of circulating exosomes as potential markers for Parkinson's disease stratification.