Contact information
| george.tofaris@ndcn.ox.ac.uk | |
| Tel | +44 (0)1865 231 295 |
| Fax | +44(0)1865 234 837 |
| PA | Jane Philips |
My connections
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New College
College
- Inhibiting Misfolded protein Propagation In Neurodegenerative Disease International consortium
- Oxford Parkinson's Disease Centre Multidisciplinary Research Centre
- Molecular Neurodegeneration Research Group Research Group
- Oxford Movement Disorders Group Research Group
Biography
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 and was appointed Clinical Lecturer at Oxford in 2007. He was awarded a Lefler fellowship from Harvard Medical School in 2008-09 for advanced studies in neurodegenerative diseases. In 2011, he completed his training in Clinical Neurology at Oxford and was awarded a Wellcome Trust Intermediate Clinical Fellowship and the Wellcome-Beit Prize. 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. He held a Todd-Bird Junior Research Fellowship in Medicine at New College. 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.
George Tofaris
PhD, MBBChir, FRCP
Wellcome Trust Clinician Scientist Associate Professor
- Honorary Consultant Neurologist
Research Summary
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 signaling 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.
Sources of Funding
- Wellcome Trust 2012- 2017
- EPSRC 2015-2018
- BMA 2015-2018
- ARUK 2015-2017
- NIHR Oxford BRC
- EU IMI 2017-2021
Key Publications
5-
Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease.
Alexopoulou Z. et al, (2016), Proc Natl Acad Sci U S A, 113, E4688 - E4697
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Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease.
Davies SE. et al, (2014), Neurobiol Dis, 64, 79 - 87
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Lysosome-dependent pathways as a unifying theme in Parkinson's disease.
Tofaris GK., (2012), Mov Disord, 27, 1364 - 1369
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Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway.
Tofaris GK. et al, (2011), Proc Natl Acad Sci U S A, 108, 17004 - 17009
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SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease.
Garcia-Reitböck P. et al, (2010), Brain, 133, 2032 - 2044
Recent Publications
5-
Concentration-Normalized Electroanalytical Assaying of Exosomal Markers.
Li Q. et al, (2017), Anal Chem, 89, 3184 - 3190
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Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson's disease.
Muhammed K. et al, (2016), Brain, 139, 2706 - 2721
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Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease.
Alexopoulou Z. et al, (2016), Proc Natl Acad Sci U S A, 113, E4688 - E4697
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ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.
Fernandes HJ. et al, (2016), Stem Cell Reports, 6, 342 - 356
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Intact Acquisition and Short-Term Retention of Non-Motor Procedural Learning in Parkinson's Disease.
Panouillères MT. et al, (2016), PLoS One, 11