4 YEAR PhD IN NEUROSCIENCE
Institute of Neurology
Mechanisms of neurodegeneration and development of therapies
Synopsis of research
Our research focuses on studying cellular mechanisms of neurodegeneration in a variety of different systems from in vitro modelling to direct study of the human disease using non-invasive neuroimaging methods, with a strong focus on Huntington’s disease and prion biology. Huntington’s disease Huntington’s disease (HD) is a devastating inherited neurodegenerative condition that arises in mid-adulthood. Our understanding of the pathogenesis of HD has expanded dramatically in recent years, and in animal models of HD many interventions can slow progression clinically and pathologically. Neuronal death is preceded by dysfunction, which may be reversible by disease-modifying therapies, resulting in clinical improvement even after the onset of symptoms. Our work focuses on (i) understanding this pre-clinical phase before overt neuronal death occurs, (ii) characterizing the effects of mutant huntingtin expression both in the periphery and centrally in a variety of model systems from cells to humans, (iii) , developing biomarkers for the evaluation of clinical trials, and (iv) developing novel therapeutic interventions. To this extent our research spans across a wide spectrum of neuroscience, to include cellular mechanisms, genetic causes, as well as brain imaging biomarkers and cognitive interventions. Prion disease Neurodegenerative diseases are one of the biggest health problems in our ageing society, and uncovering basic molecular mechanisms is fundamental for the development of therapeutics. Prion disease is the prototypical protein misfolding neurodegenerative disorder as its pathogenesis is associated with aberrant misfolding of a host cellular protein only (the protein-only hypothesis). Thus, advances in the understanding of prion pathophysiology have major implications for other neurodegenerative diseases through the elucidation of common cellular mechanisms. Our prion research focuses on cellular mechanisms of prion-mediated neurodegeneration.
Available Projects PhD projects are designed around the interests of the laboratory and can be tailored to fit the individual student. Current projects available are i) to study the role of abnormal immune activation in the early pathogenesis of Huntington?s disease, ii) to develop novel interventions to support brain plasticity and compensation in the early and pre-symptomatic stages of the disease, and iii) to model the loss of corticostriatal connectivity in HD in vitro using human iPSC derived medium spiny neurons (MSNs).
More information and publications http://www.hdresearch.ucl.ac.uk.
Selected Publications (from over150 research papers)
Sarah J Tabrizi, Rachael I Scahill, Gail Owen, Alexandra Durr, Blair R Leavitt, Raymund A Roos, Beth Borowsky, Bernhard Landwehrmeyer, Chris Frost, Hans Johnson, David Craufurd, Ralf Reilmann, Julie C Stout, Douglas R Langbehn, and the TRACK-HD Investigators. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. The Lancet Neurology, 2013 July;12(7):637-49.
Tabrizi SJ, Reilmann R, Roos RA, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Craufurd D, Hicks SL, Kennard C, Landwehrmeyer B, Stout JC, Borowsky B, Scahill RI, Frost C, Langbehn DR. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurology. 2012 Jan; 11(1):42-53.
Novak MJU, Warren JD, Henley SMD, Draganski B, Frackowiak RS, Tabrizi SJ. Altered brain mechanisms of emotion processing in premanifest Huntington’s disease. Brain. 2012 April; 135(Pt4):1165-79.
Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard C, Craufurd D, Frost C, Langbehn DR, Reilmann R, Stout JC. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurology. 2011; 10(1):31-42.
Tabrizi S.J., Langbehn D.R., Leavitt B.R., Roos R.A.C., Durr A., Craufurd D., Kennard C., Hicks S.L., Fox N. C., Scahill R.I., Borowsky B., Tobin A.J., Rosas S.D., Johnson H., Reilmann R., Landwehrmeyer B., Stout J. C and the TRACK-HD Investigators, Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data, Lancet Neurology. 2009;8(9):791-801.
Andreas Weiss, Ulrike Trӓger, Stephan Grueninger, Ruth Farmer, Christian Landles, Rachael I Scahill, Nayana Lahiri, Salman Haider, Douglas Macdonald, Chris Frost, Gillian P Bates, Graeme Bilbe, Rainer Kuhn, Ralph Andre, Edward Wild and Sarah J Tabrizi. Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. Journal of Clinical Investigation 2012. 1229(1):3731-3736.
Wanda Kwan, Ulrike Träger, Dimitrios Davalos, Austin Chou, Ralph Andre, Aaron Miller, Flaviano Giorgini, Christine Cheah, Thomas Möller, Nephi Stella, Katerina Akassoglou, Sarah J. Tabrizi, Paul J. Muchowski. Mutant huntingtin impairs immune cell migration in Huntington’s disease. Journal of Clinical Investigation. 2012;122(12):4737-4747.
P Deriziotis*, R André*, D Smith* R Goold, KJ Kinghorn, M Kristiansen, JA Nathan, R Rosenzweig, D Krutauz, M Glickman, J Collinge, AL Goldberg, SJ Tabrizi. Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry. EMBO Journal 2011;30(15):3065-3077.
R Goold, S Rabbanian,, L Sutton, R Andre, P Arora, J Moonga, AR Clarke, G Schiavo, P Jat, J Collinge, SJ Tabrizi Highly rapid cell surface prion protein conversion revealed using a novel cell system. Nature Communications. 2, 281 - 291
Maria Björkqvist, Edward J Wild, Jenny Thiele, Aurelio Silvestroni, Ralph Andre, Nayana Lahiri, Elsa Raibon, Richard V Lee, Caroline L Benn, Denis Soulet, Anna Magnusson, Ben Woodman, Christian Landles, Mahmoud A Pouladi, Michael R Hayden, Azadeh Khalili-Shirazi, Mark W Lowdell, Patrik Brundin, Gillian P Bates, Blair R Leavitt, Thomas Möller and Sarah J Tabrizi. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. Journal of Experimental Medicine, 2008 Aug 4; 205(8):1869-77. Epub 2008 Jul 14
M Kristiansen, P Deriziotis, D Dimcheff, GS.
Jackson, H Ovaa, H Naumann, F Leeuwen, V Benito, AR Clarke, NP Dantuma, JL
Portis, J Collinge, SJ Tabrizi. Disease
associated prion protein oligomers inhibit the 26S proteasome. Molecular Cell.
2007; 26 (2):175-88
*Joint senior authors