Professor Lesley Jones
Based in the Institute of Psychological Medicine and Clinical Neuroscience and the MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine
Research Keywords
Neurodegeneration, Huntington’s disease, Alzheimer’s disease, gene expression analysis, mouse models of neurodegenerative disease.
Research Interests and Facilities
Huntington’s disease (HD) is an inherited neurodegeneration caused by an expanded CAG repeat in the HD gene. This encodes a protein, huntingtin, with an expanded glutamine tract in the N terminus of the protein. The downstream effects of this mutation remain unclear although many biological systems are altered in the disease including dysregulation of gene expression, alterations in mutant huntingtin conformation and localisation, changes in energy metabolism and altered protein degradation. My group is active in a number of research areas:
- Characterisation of mouse models of HD: this work is funded by the Cure HD Foundation and is carried out in collaboration with Prof Stephen Dunnett and Dr Simon Brooks. We have been examining how closely six different genetic models recapitulateevents of the human disease in order to assess which models might be best suited to testing potential therapies for HD. We were the first group to note that the molecular profiles of gene expression were very similar in all brains across the models and that differences were largely temporal. We have followed this up examining molecular changes in brain gene expression in parallel with behavioural phenotypes in multiple HD mouse lines. We have demonstrated similarities and differences in the animals in all domains and much of the characterisation is collected into a special edition of the Brain Research Bulletin. We have confirmed that all the models examined have strong similarities in striatal gene expression and that these changes show a distinctive profile that is significantly similar to human HD brain ('Conservation of regional gene expression in mouse and human brain', 'Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage'.). We are also the first group to report a significant and substantial down-regulation of the knocked in mutant Htt gene (mHtt) in a knock in mouse line ('Longitudinal analysis of gene expression and behaviour in the HdhQ150 mouse model of Huntington's disease') and we have preliminary evidence that this is also the case in human HD brain. We are also addressing the epigenetic changes that potentially underlie the cognitive changes in models of HD.
- Huntingtin/mHTT characterisation. In parallel with the work above we have also been examining the localisation of full-length huntingtin (HTT) and mutant HTT (mHTT) in immortalisedand primary cell lines derived from the mouse models above. We have observed that growth factors stimulate the nucleo-cytoplasmic movement of Htt in cells and that this process shows differences between Htt and mHtt. We are now examining the effect of Htt phosphorylation on this process and examining the downstream effects of growth factor perturbation on primary striatal cell lines from knock in mice (Wellcome Trust studentship to K. Bowles: collaboration with R. Truant, McMaster, Ontario, Canada; J. Steffan and L. Thompson UC Irvine, CA, USA). We have also collaborated with B. Davidson, Iowa, USA, to examine the involvement of miRNAs in HD (23) and my laboratory showed that miR9/9* is downregulated in human HD brain.
- European Huntington’s Disease Network (EHDN) genetic modifiers. I am the Lead Facilitator of the Genetic Modifiers Working Group (GMWG) of the EHDN. Searching for genes that increase or delay age-of-onset or progression in HD is likely to give clues to the molecular pathways that are important in the manifestation of HD and that are therefore good therapeutic targets in HD. We are carrying out a genome-wide association study on 3500 samples, >2000 collected across Europe, (in collaboration with J. Gusella and M. MacDonald, MGH, Boston USA, S. Tabrizi, Institute of Neurology, UCL, P. Holmans, Cardiff. Alis Hughes is currently funded by EHDN to examine the collection of family history in the Registry database which will be important in post-GWAS genetic analysis.
- Alzheimer’s disease (AD). I am part of the wider AD network led by Julie Williams (link to AD research and Julie’s page) and have contributed to a number of group publications. I led the work that implicated cholesterol metabolism and innate immune involvement in disease aetiology using pathway analysis ('Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease').
External memberships and roles
- Member of EHDN since its foundation in 2007
- Member of the Scientific and Bioethical Advisory Committee (SBAC) of EHDN.
- Chair of EHDN SBAC 2010 - 2012.
- ENROLL. I am a member of the data sharing and publication working group of ENROLL.
- Member of the National Institute of Neurological Disorders and Stroke – Common Data Elements (NINDS-CDE) for HD.
- Member of
- Member of the editorial board for the Journal of Huntington’s Disease.
- Co-editor of the 4th edition of Huntington’s Disease (Oxford University Press)
School and University responsibilities
- Director of Postgraduate Research in the School of Medicine (Aug 2009)
- Chair the Research Degrees Committee (RDC) (Aug 2009)
- Member RDC (2006 - 2009)
- Director of PGR for MRC Centre 2004 - 2009
- Member, Building Capacities subcommittee of the University Graduate College
Research group members
Lyn Elliston: research technician working on CHDI funded project “A Comparative Study of Behavioural, Anatomical and Molecular Changes in Mouse Models of Huntington's Disease” £1.1M 2012 – 2014
To be appointed: postdoctoral research bioformaticist
Kathryn Bowles: WT-funded PhD student “The role of huntingtin phosphorylation in Huntington’s disease”
Jordan Scoberg-Evans: PhD student “Examining the biological basis of deteriorating cognition in Huntington’s disease”
Dr Alis Hughes: EHDN-funded postdoctoral researcher “Family History curation in HD”
Potential PhD Projects
Please contact Prof Jones if you are interested in any potential research: currently we have potential PhD projects in:
- The use of genome-wide association data to find genes that influence age of onset of Huntington’s disease.
- The correlation of gene expression and behaviour in rodent models of Huntington’s disease
- Network analysis to investigate pathways affected by the Huntington’s disease mutation
Publications
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Longitudinal analyses of operant performance on the serial implicit learning task (SILT) in the YAC128 Huntington's disease mouse line.
Brooks SP, Jones L, Dunnett SB, Brain Res Bull, Volume 88, 2-3 (June 2012) pp.130-136 -
Early onset deficits on the delayed alternation task in the Hdh(Q92) knock-in mouse model of Huntington's disease.
Trueman RC, Jones L, Dunnett SB, Brooks SP, Brain Res Bull, Volume 88, 2-3 (June 2012) pp.156-162 -
Longitudinal analysis of the behavioural phenotype in YAC128 (C57BL/6J) Huntington's disease transgenic mice.
Brooks S, Higgs G, Janghra N, Jones L, Dunnett SB, Brain Res Bull, Volume 88, 2-3 (June 2012) pp.113-120 -
Longitudinal analysis of gene expression and behaviour in the HdhQ150 mouse model of Huntington's disease.
Giles P, Elliston L, Higgs GV, Brooks SP, Dunnett SB, Jones L, Brain Res Bull, Volume 88, 2-3 (June 2012) pp.199-209 -
Proteomic changes in the brains of Huntington's disease mouse models reflect pathology and implicate mitochondrial changes.
Deschepper M, Hoogendoorn B, Brooks S, Dunnett SB, Jones L, Brain Res Bull, Volume 88, 2-3 (June 2012) pp.210-222 -
Profiles of motor and cognitive impairment in the transgenic rat model of Huntington's disease.
Fielding SA, Brooks SP, Klein A, Bayram-Weston Z, Jones L, Dunnett SB, Brain Res Bull, Volume 88, 2-3 (June 2012) pp.223-236