Title: “A multifaceted approach to disease mechanisms in common and rarer forms of Parkinsonism”
Venue: Rooms B02/B03, SITraN, 385a Glossop Road, Glossop Road, Sheffield S10 2HQ
Speaker: Dr George Tarforis, Associate Professor and Honorary Consultant Neurologist, University of Oxford
My research aim is to delineate cellular pathways in protein quality control that could inform the development of targeted therapies in neurodegenerative and neurogenetic disorders. To this end, my group uses forward genetics, proteomics and transcriptomics in models of increasing cellular complexity, including patient-derived induced pluripotent stem cells (iPSC).
Of particular interest to my group is the study of the ubiquitin pathway. 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.
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 Drosophilamodel. 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.