Contact information
+44 (0)1865 234 304
Fax +44(0)1865 234 837
Benjamin Jeffrey (NHS)
Benjamin.Jeffrey@ouh.nhs.uk
Research groups
Colleges
Websites
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Inhibiting Misfolded protein Propagation In Neurodegenerative Disease
International consortium
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Oxford Parkinson's Disease Centre
Multidisciplinary Research Centre
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. He was appointed Clinical Lecturer at Oxford in 2007 and completed his training in Clinical Neurology in 2011. Between 2008-09, he was a Lefler Fellow in Cell Biology at Harvard Medical School. 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. In 2020, he was awarded an MRC Senior Clinical Fellowship. He also 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 College and previously 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
MRC Senior Clinical Fellow, Honorary Consultant Neurologist
- Associate Professor
- Medical Research Fellow, Corpus Christi College
- Academic Lead for IMI Consortium IMPRiND
Molecular mechanisms of neurodegeneration
Research Summary
My research aim is to delineate cellular pathways in protein quality control that could inform the development of novel biomarkers and 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 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 biomarkers for Parkinson's disease prediction or stratification.
Key publications
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Serum neuronal exosomes predict and differentiate Parkinson’s disease from atypical parkinsonism
Journal article
Jiang C. et al, (2020), Journal of Neurology, Neurosurgery & Psychiatry, 91, 720 - 729
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Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1
Journal article
Jonikas M. et al, (2018), Annals of Neurology, 83, 915 - 925
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Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease
Journal article
Alexopoulou Z. et al, (2016), Proceedings of the National Academy of Sciences, 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
Journal article
Davies SE. et al, (2014), Neurobiology of Disease, 64, 79 - 87
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Lysosome-dependent pathways as a unifying theme in Parkinson's disease
Journal article
Tofaris GK., (2012), Movement Disorders, 27, 1364 - 1369
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Ubiquitin ligase Nedd4 promotes -synuclein degradation by the endosomal-lysosomal pathway
Journal article
Tofaris GK. et al, (2011), Proceedings of the National Academy of Sciences, 108, 17004 - 17009
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Pathological Changes in Dopaminergic Nerve Cells of the Substantia Nigra and Olfactory Bulb in Mice Transgenic for Truncated Human -Synuclein(1-120): Implications for Lewy Body Disorders
Journal article
Tofaris GK., (2006), Journal of Neuroscience, 26, 3942 - 3950
Recent publications
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Facile impedimetric analysis of neuronal exosome markers in Parkinson's disease diagnostics
Journal article
FU Y. et al, (2020), Analytical Chemistry
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Serum neuronal exosomes predict and differentiate Parkinson’s disease from atypical parkinsonism
Journal article
Jiang C. et al, (2020), Journal of Neurology, Neurosurgery & Psychiatry, 91, 720 - 729
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How is alpha-synuclein cleared from the cell?
Journal article
(2019), Journal of Neurochemistry
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Monitoring α-synuclein proteotoxicity in Drosophila models
Journal article
Szabo A. and Tofaris G., (2019), Methods in Molecular Biology, 1948, 199 - 208
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Convergent molecular defects underpin diverse neurodegenerative diseases
Journal article
Tofaris GK. and Buckley NJ., (2018), Journal of Neurology, Neurosurgery & Psychiatry, 89, 962 - 969
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Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1
Journal article
Jonikas M. et al, (2018), Annals of Neurology, 83, 915 - 925
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A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson’s Disease
Journal article
Tofaris GK., (2017), Journal of Parkinson's Disease, 7, 569 - 576