Professor Lesley Jones
Professor, Division of Psychological Medicine and Clinical Neurosciences
Lesley Jones has worked on neurodegenerative diseases since the 1990s. Her main work has been in Huntington’s disease (HD). HD is a rare inherited neurodegeneration caused by an expanded repeat section in the huntingtin gene on the short arm of chromosome 4. As part of a collaborative project she recently showed that the age at onset of HD and a number of other rare neurodegenerations caused by a similar repeat expansion mechanism were influenced by mechanisms related to DNA repair. She also works on Alzheimer’s disease (AD) where she has been particularly interested in pathway analyses of genetic and genomic data which have revealed new evidence implicating the immune system, endocytosis, ubiquitination and lipid metabolism in AD susceptibility.
- Member of the European Huntington’s Disease Network (EHDN) since its foundation in 2007
- Member of the Executive committee of EHDN
- ENROLL - I am a member of the data sharing and publication working group of ENROLL.
- Member of the Grant Review Board for Alzheimer’s Research UK (ARUK)
- Co-ordinator of the Cardiff Network Centre of ARUK
- 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, 2014)
- Sarah Tabrizi, University College London
- Stephen Jackson, University of Cambridge
- Jim Gusella, Marcy MacDonald and Jong-Min Lee, Massachusetts General Hospital, Harvard University
- Henry Houlden, University College London
- The International Genomics of Alzheimer’s disease Project
- Anna Barrett “Creating Cellular Models for the Functional Characterisation of Alzheimer's Disease Risk Variants” (co-supervisor with Julie Williams, Rhian Evans, Melanie Dunstan)
- Ruth Jones “Targeting Microglia in Neurodegenerative Diseases like Alzheimer’s Disease” (co-supervisor with Phil Taylor and Paul Morgan)
- Branduff McAllister “Identification and characterisation of genetic variation that modifies age at onset in Huntington’s disease” (main supervisor with Thomas Massey, Peter Holmans and Nigel Williams)
- Laura Smith, Wellcome Trust Integrated Neuroscience, “Characterising the DNA damage response in mouse models of Huntington’s disease” (main supervisor with Anne Rosser, Tom Massey and Simon Brooks)
- Jasmine Donaldson, Wellcome Trust Integrated Neuroscience, “Characterising the DNA damage response in cellular models of Huntington’s disease” (main supervisor with Tom Massey and Nick Allen)
- External co-supervisor for Davina Hensman-Moss (UCL) and Michael Flower (UCL)
- MRC International Mouse Phenotyping Consortium (IMPC) Pump Prime Award (1/11/2016-31/10/2018). “IMPC: Characterisation of a novel Alzheimer’s disease susceptibility locus”. P.Taylor (Lead) with L. Jones, M. Hill & B.P. Morgan. £24,024
- ARUK equipment bid A High Content Analysis Platform for analysing dementia-associated genetic variation. £108K. Awarded subject to part-funding from the University
- Wellcome Trust PhD studentship “DNA repair in Huntington’s disease and other repeat-associated disorders.” 109088/Z/15/A 2016 – 2019
- Wellcome Trust PhD studentship “Characterising the effects of genetic modifiers of Huntington's disease in the R6/1 HD mouse model. 109087/Z/15/A 2016 – 2019
- School of Medicine PhD award “Identification and characterisation of genetic variation that modifies age at onset in Huntington’s disease”. 2016 – 2019
- MRC Momentum award, July 2016. Dementia Research Centre: £600K (Thomas (PI), Graham, Williams, Jones, Taylor, Morgan)
- ARUK network centre grant: Cardiff. PI. £40K, Sept 2016 – Aug 2017
- EHDN Seed fund: Identification of coding variants in DNA repair genes affecting the age at onset of Huntington's Disease. (Massey, Jones, Rosser), £28K. Sept 2016 – Aug 2017
- CHDI: Genetic analysis of HD GWAS. PI £141K, 24m, Feb 2016 – Jan 2018
- EHDN seed fund: The role of DNA repair in Huntington’s disease. Jones, Massey, Rosser, Jackson £30K, June 2016 – May 2017
- MRC Confidence in Concept. Investigating the therapeutic potential of manipulating DNA repair in Huntington’s disease. £47K, Jones, Rosser, Jackson. Aug 2015 – Nov 2016
- MRC Centre “The Centre for Neuropsychiatric Genetics and Genomics” Co-applicant (the MRC Centre for Neuropsychiatric Genetics and Genomics MR/L010305/1, 2014-2019, £1.7M
- Centre for Ageing and Dementia. NISCHR Centre application, led by Vanessa Burholt, Swansea. £1.8m total. 2015 – 2018. Co-applicant.
- MRC Fellowship awarded to Dr Thomas Massey “Understanding the role of DNA repair in Huntington’s disease pathogenesis: towards novel therapeutic targets” £304,780
- Association of British Neurologists to Dr Thomas Massey “The role of DNA repair in Huntington's Disease pathogenesis.” Aug 2016 – Aug 2019 £30,000
- Brain: fellowship awarded to Dr Davina Hensman (UCL). Co-applicant. £50K. 2014 – 2016.
My group is active in a number of research areas:
Genetic modifiers in Huntington’s disease
We identified the first genetic modifiers in HD in 2015 (GeM-HD http://dx.doi.org/10.1016/j.cell.2015.07.003). Our motivation in this study was to identfy variation that could delay or precipitate disease onset as pathways that this variation lies in are ideal therapeutic targets, as we know they have this effect in people carrying the mutation. We are extending this study in collaboration with Jim Gusella, Marcy MacDonald and Jong-Min Lee (MGH, Boston USA). I am also the Lead Facilitator of the Genetic Modifiers Working Group (GMWG) of the European Huntington’s Disease Network. I collborate closely with SarahTabrizi (Institute of Neurology, UCL) and Peter Holmans, in Cardiff to integrate genetic and gene expression data from HD subjects to explore underlying pathology important in disease (10.1093/hmg/ddw142). In collboration with Sarah Tabrizi, Henry Houlden, Alexandra Durr and other collaborators we also showed that the signal we saw modifying onset in HD modifies onset in a series of spinocerebellar ataxias also caused by repeat expansion mutations (10.1002/ana.24656).
Characterisation of mouse models of HD
This work was funded by the Cure HD Foundation and is carried out in collaboration with Prof Steve Dunnett and Dr Simon Brooks. We have been examining how closely six different genetic models recapitulate events 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 ( 1 ). 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 ( 2 and 3 ). 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 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.
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. Alis Hughes is exploring the splicing of HTT in mouse and human brain (10.1016/j.jmb.2013.12.028, 10.3233/JHD-150151).
Alzheimer’s disease (AD)
I am part of the wider AD network led by Prof Julie Williams 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 (10.1038/mp.2015.23). I have been collborating with Phil Taylor and Paul Morgan in the Systems Immunity University Research Institute to examine the mechanism underlying the immune signal in AD.