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UCL Division of Biosciences

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Neuroscience - Elizabeth Fisher

Elizabeth Fisher

Institute of Neurology

Our research interests lie in creating and characterising mouse models to find the underlying defects in cellular pathways that cause degeneration and death of motor neurons. This is with particular relevance to two deficits: (1) the motor neuron disease amyotrophic lateral sclerosis (ALS) and (2) the Alzheimer's disease that arises as a result of Down syndome. Our research entails collaboration with experts within and outside UCL internationally to dissect specific biological questions. We are in an excellent, well-funded multidisciplinary environment for carrying out research along the continuum from mutation to phenotype. We believe that this research will help us to understand the relatively common, cruel and intractable diseases that cause neuron cell death.

Motor neuron degeneration disease models

We have are creating new models for the type of ALS that arises from mutations in a gene called FUS. We have are continuing to refine our genome engineering (in collaboration with MRC Harwell) and to now characterise our new ALS model, to determine the molecular changes that arise with disease, and the timing of these changes. This entails studying how mutant FUS, an RNA binding protein, behaves, and related studies such as RNA trafficking in our mouse model.

Alzheimer's disease in Down syndrome models

The biggest single genetic risk factor for Alzheimer disease is to have Down syndrome, which arises from trisomy of chromosome 21. While it is clear that having three copies of the APP gene (that lies on chromosome 21) is causal, there are aspects of the phenotype, probably including protective features, which are modulated by trisomy of other genes on chromosome 21. Using novel mouse models and crosses, we have identified a set of proteins that are altered in AD and modulated by trisomy. We are following up this finding by further investigating the cellular and biochemical pathways involved.

AVAILABLE PROJECTS

1) Helping to characterise our latest FUS mouse model. Several possible projects including training in histology or RNA analysis or biochemical analysis of mouse models of neurodegeneration. Open for discussion.

2) An investigation of APP expression and potential neurodegeneration in a mouse model of Down syndrome. Again, several possible projects, mainly cell biology/biochemistry based, to drill down into the phenotypes we have already found.

Further reading: http://www.ucl.ac.uk/ion/articles/archive-2009/Oct7

SELECTED PUBLICATIONS

Hall, J.H., Wiseman, F.K., Fisher, E.M.C., Tybulewicz, V.L.J., Harwood, J.L., Good, M.A. (2016) Tc1 mouse model of trisomy-21 dissociates properties of short- and long-term recognition memory. Neurobiology of Learning and Memory. 130, 118-128.

Joyce, P.I., Fratta, P., Landman, A., McGoldrick, P., Wackerhage, H., Groves, M., Busam, B.S., Galino, J., Corrochano, S., Beskina, O.A., Esapa, C., Ryder, E., Carter, S., Stewart, M., Codner, G., Hilton, H., Teboul, L., Lionikas, A., Estabel, J., Ramirez-Solis, R., White, J.K., Tucker, J., Brandner, S., Plagnol V., Bennett, L.H., Abramov, A.Y., Greensmith, L., Fisher, E.M.C.*, Acevedo-Arozena, A.* (2015) Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration. Hum Molec Genet. 25: 291-307 doi: 10.1093/hmg/ddv471

Witton J., Padmashri R., Zinyuk L.E., Popov V.I., Kraev I., Line S.J., Jensen T.P., Tedoldi A., Cummings D.M., Tybulewicz V.L.J., Fisher E.M.C., Bannerman, D.M., Randall, A.D., Brown J.T., Edwards F.A., Rusakov D.A., Stewart M.G.,Jones M.W. (2015) Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome. Nature Neurosci 18: 1291-1298. doi:10.1038/nn.4072

Wiseman, F.K., Al-Janabi, T., Hardy, J., Karmiloff-Smith, A., Nizetic, D., Tybulewicz, V.L.J, Fisher, E.M.C.*, Strydom, A. (2015) A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nature Reviews Neuroscience, 16: 564-574 doi:10.1038/nrn3983

O Doherty, A., Ruf, S., Mulligan, C., Hildreth, V., Errington, M.L., Cooke, S., Sesay, A., Modino, S., Vanes, L., Hernandez, D., Linehan, J.M., Sharpe, P.T., Brandner, S., Bliss, T.V.P., Henderson, D.J., Nizetic, D., Tybulewicz, V.L.J., Fisher, E.M.C. (2005) Germline transmission of an almost complete, freely segregating human chromosome 21 in a mouse strain that models aspects of Down syndrome. Science 309: 2033-2037 More: https://iris.ucl.ac.uk/research/personal?upi=EMCFI97


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