Investigating the potential toxicity of tau fragments specifically present in progressive supranuclear palsy brain
Lead researcher Dr Diane Hanger
Co-researchers Selina Wray (Research Assistant); Dr Tamas Revesz and Dr Janice Holton
Institution MRC Centre for Neurodegeneration Research,
King's College London, Institute of Psychiatry
Duration 1 year
Start November 2007 End November 2008
Grant £32,200
Aim of research
• Identify absolute N-terminus of tau fragment in PSP brain
• Express identical tau fragment in cells
• Determine the aggregatory characteristics of this fragment in comparison with full length tau
• Determine the phosphorylation state of this fragment
• Determine if the tau fragment is cytotoxic
About the research
We have carried out a biochemical characterization of insoluble tau from post-mortem brain tissue of PSP and other related disorders with tau pathology. This led us to the discovery of a C-terminal fragment of tau that is specific to PSP and closely-related disorders where 4R tau isoforms are present in excess. In order to investigate what role this fragment could play in the pathogenesis of these disorders, we have generated a construct to allow overexpression of the tau fragment in cells. This has allowed us to investigate the state of aggregation of the tau fragment, as well as its phosphorylation status and toxicity using standard assays. As the fragment is specific to a subset of disorders with tau pathology, we also aimed to investigate its potential as a diagnostic tool, by determining if it is present in CSF and also by generating an antibody to the fragment which could allow more confident diagnosis at post-mortem.
Findings
The results of this work are currently being analysed. An update on the findings will follow shortly.
What does the outcome of this research mean for people with PSP?
The results of this research may reveal a new cellular model of PSP that is based on our previous discovery of a tau fragment in human PSP brain tissue. Such models are urgently required in this research field since few exist at present and disease-related models could be used in the future to test new therapies that target tau aggregation.
Publications arising from this work
Manuscript in preparation.
Tau Phosphorylation Article - 'Trends in Molecular Medicine', Mar 09
National/international presentations given on this work
Wray, S., Anderton, B.H. and Hanger, D.P. Potential toxicity of Tau cleavage products in progressive supranuclear palsy. 11th International conference on Alzheimer's disease and related disorders, Chicago, USA. July 25-31, 2008.
Wray S., Anderton B.H. and Hanger D.P. Tau phosphorylation and cleavage in progressive supranuclear palsy. 6th forum of European Neuroscience, Geneva, Switzerland, July 12-16, 2008.
Hanger D. P., Wray S., Seereeram A., Noble W and Anderton B. H. Protein phosphorylation and tau kinases implicated in the tauopathies. MRC Showcase: Breakthroughs in neuroscience and mental health, Bristol, UK, February, 2008.
Weblinks
King's College London, staff
MRC Centre for Neurodegeneration Research
How has the research you conducted influenced your career and research direction?
We have recently submitted a four year grant application to the Medical Research Council to continue and extend this work. The new project would include the generation of new cellular and animal models of tau deposition in neurodegenerative disease, including PSP.