Corpus Christi College Oxford

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Dr George Tofaris
 

Biography

I graduated from the combined MB/PhD programme of Cambridge University, Trinity College, and completed my general medical training at the National Hospital for Neurology, Hammersmith, Royal Brompton and Royal Free hospitals in London. I 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. Between 2008-09, I was a Lefler research fellow at Harvard Medical School. I completed my training in Clinical Neurology in 2011 and subsequently awarded a Wellcome Trust Intermediate Clinical Fellowship and the Wellcome-Beit Prize to establish my research group at Oxford. I am the academic lead for 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.  As a clinically active Consultant Neurologist at the John Radcliffe hospital, I cover acute as well as general outpatient neurology and lead regional specialist clinics in Movement and Neurogenetic Disorders.

Research Interests

My research investigates cellular mechanisms that regulate the clearance of misfolded proteins or damaged organelles in age-related neurodegenerative and rare neurogenetic disorders with a primary focus on Parkinson’s disease.  An important signalling cascade in this respect is the conjugation of a ubiquitin chain to protein-substrates or organelles such as mitochondria. I previously demonstrated that the key pathogenic protein in Parkinson’s disease, called α-synuclein, is degraded in a ubiquitin-dependent manner and identified relevant enzymes that mediate this process. My research group is currently employing a multifaceted approach encompassing forward genetics, proteomics and transcriptomics in models of increasing cellular complexity, including the use of patient-derived induced pluripotent stem cells (iPSC) to:

(1) Map the relevant enzymes that regulate alpha-synuclein homeostasis or dopaminergic cell viability more broadly
(2) Understand how disruption of these mechanisms leads to disease
(3)Translate this fundamental knowledge into rational mechanism-based therapies

In collaboration with the Department of Chemistry in Oxford, we are also investigating the role of exosomes as biomarkers of Parkinson’s disease progression. 

Key Publications

Jonikas M, Madill M, Mathy A, Zekoll T, Zois CE, Wigfield S, Kurzawa-Akanbi M, Browne C, Sims D, Chinnery PF, Cowley SA, Tofaris GK. Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1. Ann Neurol. 2018 May;83(5):915-925.

Li Q, Tofaris GK, Davis JJ. Concentration-Normalized Electroanalytical Assaying of Exosomal Markers. Anal Chem. 2017 Mar 7;89(5):3184-3190.

Alexopoulou Z, Lang J, Perrett RM, Elschami M, Hurry ME, Kim HT, Mazaraki D, Szabo A, Kessler BM, Goldberg AL, Ansorge O, Fulga TA, Tofaris GK. Deubiquitinase Usp8 regulates alpha-synuclein clearance and modifies its toxicity in Lewy body disease. Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):E4688-97.

Tomlinson PR, Zheng Y, Fischer R, Heidasch R, Gardiner C, Evetts S, Hu M, Wade-Martins R, Turner MR, Morris J, Talbot K, Kessler BM, Tofaris GK. Identification of distinct circulating exosomes in Parkinson's disease. Ann Clin Transl Neurol. 2015 Apr;2(4):353-61.

Davies SE, Hallett PJ, Moens T, Smith G, Mangano E, Kim HT, Goldberg AL, Liu JL, Isacson O,Tofaris GK. Enhanced ubiquitin-dependent degradation by Nedd4 protects against alpha-synuclein accumulation and toxicity in animal models of Parkinson's disease. Neurobiol Dis. 2014 Apr;64:79-87.

Tofaris GK. Lysosome-dependent pathways as a unifying theme in Parkinson's disease. Mov Disord. 2012 Sep 15;27(11):1364-9.

Tofaris GK, Kim HT, Hourez R, Jung JW, Kim KP, Goldberg AL. Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway. Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17004-9.

Garcia-Reitböck P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, Della Corte L, Spano P, Tofaris GK, Goedert M, Spillantini MG. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain. 2010 Jul;133(Pt 7):2032-44.

Links

www.ndcn.ox.ac.uk/team/george-tofaris

www.ndcn.ox.ac.uk/research/molecular-neurodegeneration-research-group

www.imprind.org


 

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