Professor Peter St George Hyslop FRS

Genetics of human neurodegenerative disease

General audience summary:
Neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease share the common feature of neuronal cell death, or neurons that have lost their structure and function in the central nervous system. This group of diseases often show abnormal folding of particular neuronal proteins, resulting in toxic aggregate formation. Through detailed DNA analysis of large groups of patients, we have determined the DNA changes that increase susceptibility to development of specific disease types. We are also interested in the mechanisms by which protein aggregates form, and how changes in protein function might increase the development of neurodegenerative disease.

Strategic CIMR themes: Neurological Diseases, Rare Genetic Diseases

Funding: Wellcome Trust, Medical Research Council, National Institutes of Health Research (USA)

Research Group members: Michael Fernandopulle, Deniz Ghaffari, James Henderson, Janin Lautenschlager, William Meadows, Jonathon Nixon-Abell, Seema Qamar

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Research

My laboratory focuses upon understanding the causes and molecular mechanisms of neurodegenerative diseases such as Alzheimer disease, Parkinson disease and fronto-temporal dementia. We and others have shown that these diseases are frequently caused by the accumulation neurotoxic proteins or protein fragments. We employ genetic, molecular biological, cell biological, and animal modelling strategies to: 1) identify disease-causing genes; and 2) identify the molecular pathways by which these mutations or polymorphisms lead to neuronal death.

We have used a battery of techniques to identify and then investigate the biology of genes associated with human neurodegenerative disease, and with Alzheimer disease in particular. Thus we have used GWAS and/or whole exome sequencing methods to identify more than 10 different genes associated with late-onset Alzheimer’s disease, fronto-temporal dementia or progressive supranuclear palsy. We have then modelled these genes and their proteins using structural biology, cellular and invertebrate model organisms. Thus, we have shown that the presenilins form a dynamic complex, and we have deduced how substrates gain access to these complexes3. We have shown that FUS and TDP43 form a novel type of hydrogel-dependent neurotoxic intracellular protein aggregate. We have shown that TREM2 mutants alter TREM endoproteolytic cleavage and signalling.

Publications

Key publications:

Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P. ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron 88, 678-690 (2015).

Li, Y., Lu, S.H.J.,Tsai, C.J., Bohm, C., Qamar, S., Dodd, R.B., Meadows, W., Jeon, A., McLeod, A., Chen, F., Arimon, M., Berezovska, O., Hyman,B.T., Tomita, T., Iwatsubo, T., Johnson,C.M., Farrer, L.A., Schmitt-Ulm, G., Fraser, P.E. and St George-Hyslop, P.E. Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes. Structure 22, 125–135 (2014).

Lambert, J.C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature Genet. 45, 1452–1458 (2013).

Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J.S., Younkin, S., Hazrati, L., Collinge, J., Pocock, J., Lashley, T., Williams, J., Lambert, J.C., Amouyel, P., Goate, A., Rademakers, R., Morgan, K., Powell, J., St George-Hyslop, P., Singleton, A., Hardy, J. and Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

Genetics of human neurodegenerative disease

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Research

Publications

Contact Details

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Study at Cambridge

About the University

Research at Cambridge