George Tofaris graduated from the combined MB/PhD programme of Cambridge University in 2003. He completed his general medical training at the National Hospital for Neurology, Hammersmith, Royal Brompton and Royal Free hospitals in London in 2006. He worked for a year at the Neurology Department of the Austin hospital, an affiliate of Melbourne University. He was appointed Clinical Lecturer at Oxford in 2007 and completed his training in Clinical Neurology in 2011. Between 2008-09, he was awarded a Lefler fellowship from Harvard Medical School for advanced studies in neurodegenerative diseases. In 2012, he was awarded a Wellcome Trust Intermediate Clinical Fellowship and the Wellcome-Beit Prize to further his research and after a short visit at the Brigham and Women's Hospital in Boston, he established his research group at Oxford. He heads the EU IMI Consortium IMPRiND which aims to delineate new mechanisms that are relevant to the progression of pathology in Parkinson's and Alzheimer's disease. He is a Medical Research Fellow at Corpus Christi and previously held a Todd-Bird Junior Research Fellowship in Medicine at New College. He was the recipient of the biennial Cornelli Prize for research in Parkinson's disease and the Junior Investigator Award from the International Movement Disorder Society. As a clinically active Consultant Neurologist at the John Radcliffe hospital, he covers acute as well as general outpatient neurology and leads regional specialist clinics in Movement and Neurogenetic Disorders.
PhD, MBBChir, FRCP
Associate Professor and Honorary Consultant Neurologist
Molecular mechanisms of neurodegeneration
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 found that α-synuclein is ubiquitinated in human brain and discovered that this modification regulates the trafficking of α-synuclein to endosomes for degradation by lysosomes. We identified the E3 ligase NEDD4 and the deubiquitinase USP8 as two enzymes that regulate this process and showed in animal models that they modify α-synuclein-induced toxicity. 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.