4 YEAR PhD IN NEUROSCIENCE
Institute of Neurology
Cellular mechanisms of neurodegeneration
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, with a strong focus on Huntington’s disease and prion biology.
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 understanding this pre-clinical phase before overt neuronal death occurs and the effects of mutant huntingtin expression both in the periphery and centrally in a variety of model systems from cells to humans.
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.
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, and ii) to dissect the interaction between prions and the ubiquitin-proteasome system (UPS) and its relevance to other neurodegenerative diseases.
More information and publications:
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 (2008)
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 (2007)
Disease associated prion protein oligomers inhibit the 26S proteasome.
Molecular Cell. 2007; 26 (2):175-88
Runne H, Kuhn A, Wild E, Pratyaksha W, Kristiansen M, Isaacs J, Régulier E, Delorenzi M, Tabrizi S.J.*, Luthi-Carter R*. (2007)
Analysis of potential transcriptomic biomarkers for Huntington’s disease in peripheral blood.
Proc Natl Acad Sci USA. 2007 ;104(36):14424-9
*Joint senior authors