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Prof Gill Bates

Professor of Molecular Neuroscience

Neurodegenerative Diseases

UCL Queen Square Institute of Neurology

Joined UCL
1st Mar 2016

Research summary

Huntington’s disease is an inherited neurodegenerative disorder that manifests with psychiatric symptoms, uncontrolled movements and cognitive decline. It is caused by a CAG repeat expansion in the huntingtin gene (HTT) that leads to a polyglutamine expansion in the huntingtin protein (HTT). The research in the Bates lab is aimed at understanding the molecular events that are triggered by the HD mutation at the DNA, RNA and protein levels, and validating these as therapeutic targets.

 

The CAG repeat that causes HD is somatically unstable and in 1997, the Bates lab published the comparative levels of somatic instability in brain regions and peripheral tissues in HD mouse models. In the intervening years, it has been shown by others that this DNA instability is dependent on the presence of specific DNA repair proteins, and more recently, some of these DNA repair genes have been identified as genetic modifiers in GWAS studies. With Sarah Tabrizi, we are currently investigating the extent to which somatic instability contributes to HD pathogenesis, and hence the therapeutic potential of targeting CAG repeat instability.

The Bates lab found that exon 1 of HTT does not always splice to exon 2, resulting in the production of a small polyadenylated transcript that encodes the highly pathogenic exon 1 HTT protein. This aberrant splicing event occurs in all knock-mouse models of HD, in mice transgenic for human HTT in the form of a yeast or bacterial artificial chromosome and in HD patient post mortem brains and fibroblast lines. The level of incomplete splicing increases with the size of the CAG repeat expansion. We are currently investigating the mechanisms that cause this incomplete splicing event and the extent to which the generation of this exon 1 transcript contributes to HD pathogenesis.  

The exon 1 HTT protein aggregates readily and is likely to be the HTT species that nucleates HTT aggregation in mouse models and HD patient tissues. We are working with Erich Wanker (Max Delbruck Centre, Berlin) and Gabriella Kaminski (University of Cambridge) to understand the nature of HTT seeding and polymerisation and to be able to measure and define the onset of this process in HD mouse models. We have a long-standing interest in the proteostasis networks that maintain the solubility of the HTT protein, with a particular focus on the heat shock response, that we have shown becomes dysregulated with disease progression in HD. 

We are investigating therapeutic approaches that lower the levels of HTT transcripts and are working with scientists at the CHDI Foundation to enable these projects. We are particular interested in those that target the small exon 1 – intron 1 mRNA. These are being pursued in collaboration with Ben Deverman (Caltech), Anastasia Khvorova (University of Massachusetts Medical School) and Frank Bennett (Ionis Pharmaceuticals). We are working with Paul Whiting at the Drug Discovery Institute at UCL, to identify small molecules to enhance HTT splicing.   

Teaching summary

Bates organised and taught on the Neurogenetics module for the School of Medicine Intercalated BSc in Genetics at King’s College London from 1999 – 2012. Since 1990, she has given lectures and tutorials on 14 BSc and MSc courses for periods ranging from between 2 and 12 years. Her lab has hosted multiple MSc and BSc students for their research projects, being committed to offering at least two projects per year. She acted as Chief External Examiner for the MSc in Medical Genetics with Immunology at Brunel University from 2001 – 2005 and External Examiner on the MSc in Clinical Neuroscience at the Institute of Neurology, UCL from 2002 to 2006. As of December 2107, 12 PhD students have been awarded their research degrees for projects undertaken with Bates as primary supervisor.

Education

St Mary's Hospital Medical School
PhD, Molecular Biology and Genetics | 1987
Birkbeck College
MSc (Hons), Biomolecular Organisation | 1984
Sheffield University
BSc, Genetics | 1979

Biography

Bates obtained a first class BSc in Genetics from Sheffield University in 1979 and an MSc in Biomolecular Organisation from Birkbeck College in 1984. Her interest in human genetics, and the possibilities of identifying the mutations causing genetic diseases, led her to Bob Williamson’s Department at St. Mary’s Hospital Medical School as a research assistant in 1983, where she then carried out her PhD on the molecular genetics of cystic fibrosis. In 1987, she moved to Hans Lehrach’s laboratory at the Imperial Cancer Research Fund, as a postdoctoral fellow, to work on Huntington’s disease (HD). The Lehrach lab was working toward the identification of the HD mutation as a part of an international collaborative research group under the umbrella of the Hereditary Disease Foundation, led by Nancy Wexler. Bates led a small group that performed the physical mapping and large scale cloning for this combined endeavour, which led, in 1993, to the identification of the HD mutation as a CAG repeat expansion. In 1994, Bates moved to the Department of Medical and Molecular Genetics at the United Medical and Dental Schools as a Senior Lecturer to establish her independent research group investigating the molecular basis of Huntington’s disease. Her lab published the first mouse models of HD in 1996, which, with Stephen Davies, led to the identification of HTT inclusions in 1997, and in 1998, the first indication of transcriptional dysregulation in HD by Jang Ho Cha. Bates became Professor of Neurogenetics at King’s College London in 1998 and Head of the Division of Genetics and Molecular Medicine at KCL in 2011. In 2016, she moved her lab to the Institute of Neurology at University College London to establish the Huntington’s Disease Centre with Professor Sarah Tabrizi. She is Professor of Molecular Neuroscience at the Institute of Neurology and the UCL Dementia Research Institute, Co-Director of the Huntington’s Disease Centre and Vice-Dean (Research) for the Faculty of Brain Sciences. She was elected to the Academy of Medical Sciences in 1999, the European Molecular Biology Organisation in 2002 and the Royal Society in 2007.

Publications