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Professor Lesley Jones

Professor Lesley Jones

Professor, Division of Psychological Medicine and Clinical Neurosciences

School of Medicine

Email:
jonesl1@cardiff.ac.uk
Telephone:
+44 (0)29 2068 8469
Location:
3.08, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ
Available for postgraduate supervision

My laboratory has been working on Huntington's disease (HD) using genetics, bioinformatics, cell and animal models. HD is an inherited disease caused by an expanded repeated section of DNA and the length of the repeat partly determines age-at-onset of disease.  I am particularly interested in genetic modifiers of HD. Genetic variation that modifies disease can be regarded as a therapeutic target since it modifies the disease in people. We showed that DNA repair mechanisms and the exact CAG repeat sequence alter HD age-at-onset and are investigating how this might cause HD in our model systems in the laboratory.

Genetic profiling: the key to Huntington’s treatment?

An interview at the Alzheimer's Research UK Conference 2019.

https://youtu.be/7sKBJmhuuBo

Current post (2012 - )    

Professor of Neuropsychiatric genetics, Div Psychological Medicine Clinical Neuroscience and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University. HEFCW funded. Reader (2007), Senior Lecturer (1999).

Education:

BSc (hons) Biochemistry 1st class (1985): PhD (1990). Cardiff University. I am not clinically qualified.

 

Honours and awards

Selected recent invited presentations

    • June 2019: co-chair and session lead, Gordon Research Conference CAG Trinucleotide repeats;
    • March 2019: Invited speaker Alzheimer’s Research UK, Harrogate, UK;
    • Nov 2018: invited speaker, GlasgowNeuro conference, Royal Coll. Surgeons, Glasgow;
    • April 2018: invited speaker, Genomics of Brain Disorders meeting, Wellcome Trust Sanger Centre;
    • Oct 2017: invited speaker NINDS “Biomarkers in HD”, NIH, Washington, USA;
    • June 2017: invited speaker, CAG Triplet Repeats Gordon Conference, Mount Snow, Vermont, USA;

Professional memberships

Collaborations

I collaborate closely with many of my colleagues locally in the MRC Centre for Neuropsychiatric Genetics and Genomics, the Institute for Neuroscience and Mental Health and the wider College of Biomedical and Life Sciences. In particular I collaborate with Peter Holmans, Vincent Dion, Nigel Williams, Valentina Escott-Price, Georgina Menzies, Gaynor Smith, Julie Williams, Rebecca Sims, John Atack and Simon Ward.

Externally I collaborate with:

  • Sarah Tabrizi, University College London
  • Gill Bates, 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
  • Darren Monckton, University of Glasgow
  • Lorena Beese, Duke University School of Medicine
  • Ray Truant, McMaster University
  • Bob Lahue, National University of Ireland

PhD students

  • 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): 2016
  • 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): 2016
  • Anthony Warland, MRC funded "Characterising the dynamics of repeat expansion in Huntington’s disease" (main supervisor with Tom Massey and Nigel Williams): 2018
  • Freja Sadler, UKDRI funded "Characterising the pathways to abnormal protein aggregation in dementia in Drosophila and induced pluripotent stem cell models" (main supervisor with Gaynor Smith, Tom Massey and Emyr Lloyd-Evans): 2018
  • Laura Heraty, UKDI co-supervisor with Vincent Dion, 2019
  • External co-supervisor for Davina Hensman-Moss (UCL) and Michael Flower (UCL)

Current Funding

  1. LoQus23 Therapeutics. MSH3: a disease modifying approach to Huntington’s disease. Jones (PI), Massey, Ward, Atack. 2019 – 2020 (18m), £535,349.
  2. CHDI. Integrating genetic and functional data to identify pathogenic pathways modifying the progression and phenotypic expression of Huntington's disease. Holmans (PI), Jones. May 2019 – April 2021 (24m): £353,485.          
  3. CHDI. Pilot investigation to characterise the in vitro and in vivo effects of FAN1 in Huntington’s disease. Jones (PI), Massey, Allen.  2018 – 2020 (24m), £468,543.
  4. MRC PhD studentship “Characterising the dynamics of repeat expansion in Huntington’s disease” Jones (PI), Williams N, Massey T. (Oct 2018 – Sept 2021) £85,000;
  5. UKDRI PhD studentship “Biological dissection of phenotypic heterogeneity in HD” Jones (PI), Smith G, Massey T, Lloyd-Evans E. (Oct 2018 – Mar 2022) £100,000;
  6. ARUK “ARUK-PPG2018A-015 “Detecting simple repeat sequences in the genome and their effects in dementias.” £48,507 Jones L (PI), Holmans P, Sims R, Williams N. (2018 –2019);
  7. Wellcome Trust PhD studentship “DNA repair in Huntington’s disease and other repeat-associated disorders.” 109088/Z/15/A 2016 – 2019. £150,321;
  8. MRC Fellowship Dr Thomas Massey “Understanding the role of DNA repair in Huntington’s disease pathogenesis: towards novel therapeutic targets” £304,780 Aug 2016 – July 2019
  9. Association ofBritishNeurologists Dr Thomas Massey “The role of DNA repair inHuntington's Diseasepathogenesis.”Aug 2016 – Aug 2019 £30,000
  10. School of Medicine PhD award “Identification and characterisation of genetic variation that modifies age at onset in Huntington’s disease”. 2016 – 2019. £82,000
  11. MRC Momentum award, May 2017 – Apr 2020. Dementia Research Centre: £962,670K (Thomas (PI), Graham, Williams, Jones, Taylor, Morgan);
  12. 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;

Speaking engagements

2020

  • May 2020: invited speaker, Huntington's disease Youth Association meeting, Glasgow, UK

2019

  • Nov 2019: invited speaker, Bristol Neuro conference, Bristol;
  • Nov 2019: invited seminar, National University of Ireland, Galway 2019:
  • April 2019: invited speaker Alzheimer’s Research UK annual conference, Harrogate, UK

https://youtu.be/OJdPmz4H5SY

https://youtu.be/EWFLSBYava0

2018

  • Nov 2018: invited seminar, Glasgow Neuro Society, Glasgow;
  • Oct 2018: invited seminar, Universite de Lausanne, Center for Integrative Genomics;
  • Sept 2018: invited speaker, EHDN Plenary meeting, Vienna;
  • May 2018: invited speaker, Enroll-HD Congress, Quebec, Canada;
  • May 2018: invited participant/presenter “Tackling gaps in developing life-changing treatments for dementia”, ARUK, London;
  • April 2018: invited speaker, The 9th Intl Conf on Unstable Microsatellites & Human Disease, Italy;
  • April 2018: invited speaker, Genomics of Brain Disorders meeting, Wellcome Trust Sanger Centre;

2017

  • Dec 2017: invited speaker NECTAR meeting, Dublin, Dec 2017;
  • Oct 2017: invited speaker NINDS “Biomarkers in HD”, NIH, Washington, USA;
  • June 2017: invited speaker, CAG Triplet Repeats Gordon Conference, Mount Snow, Vermont, USA;

Committees and reviewing

External roles and responsibilities

  • Chair of internal Wellcome Trust ISSF panel
  • Member, Programme committee, Alzheimer’s Research UK conference 2020.
  • Member, Executive Committee of the European Huntington’s Disease Network (EHDN), 2014 – 2022.
  • Programme chair, EHDN Plenary meeting Vienna, Sept 2018.
  • Chair Gordon conference “CAG trinucleotide repeats” June 2021 (vice-chair 2019).
  • Member Alzheimer’s Research UK Scientific Advisory Board (2013 - ).
  • Member Huntington Society of Canada Research Board (2016 - )
  • Member FRIMEDBIO Panel 7 (Neuroscience) Research Council of Norway (2017 - ).

I regularly review for grant boards and journals nationally and internationally. 

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Genetic modifiers in Huntington’s disease

Our latest research just published in Cell (https://www.sciencedirect.com/science/article/pii/S0092867419307391) follows up our first analysis of genetic modifiers in HD from 2015 (GeM-HD http://dx.doi.org/10.1016/j.cell.2015.07.003). Our latest data indicate that not only are pathways involved in DNA handling and repair involved in altering the age at which people get Huntington's disease, but that the sequence of the disease-causing CAG repeat is critical too. Most people - whether or not they have HD - have two copies of a CAG repeat that has a CAACAG hexamer at the 3' end. In a few people though, the repeat has a different sequence at the 3' end: people with expanded CAG repeats with CAACAGCAACAG at the 3' end get Huntington's disease much later than expected, whereas people with no CAA repeat at all, just a pure CAG, get the disease much earlier than expected. This is because the repeat lengths are being measured incorrectly, and it is the pure CAG length rather than the translated HTT protein polyglutamine length that is important, but is also likely due to other factors, potentially related to the structures in the DNA adopted by the repeats of different sequences.

Our motivation in these studies was to identify variation that could delay or precipitate disease onset as the biological 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, Vanessa Wheeler and Jong-Min Lee (MGH, Boston USA), Seung Kwak (CHDI, USA) and Michael Orth (Ulm University, Germany). I was also the Lead Facilitator of the Genetic Modifiers Working Group (GMWG) of the European Huntington’s Disease Network. I collaborate 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 collaboration 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). This implicates the expansion in the DNA as the main source of modification of the age of onset in these diseases, rather than more downstream events.  We went on to demonstrate that variation in MSH3 on chromosome 5 is associated with how fast HD progresses (.https://doi.org/10.1016/S1474-4422(17)30161-8). We are now exploring how these genes affect HD using cellular and animal models of disease with funding from CHDI, the Dementia Discovery Fund, the Wellcome Trust and the MRC.

Alzheimer’s disease (AD)

I led the work that implicated cholesterol metabolism and innate immune involvement in disease aetiology using pathway analysis (10.1038/mp.2015.23) and the follow up analysis in the International Genomics of Alzheimer's disease Project (IGAP) (https://doi.org/10.1016/j.jalz.2014.05.1757). 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.

HD lab group members

Tom Massey: clinical neurologist, WCAT, MRC and Philip Berthold research fellow

Lyn Elliston: research technician

Sergey Lobanov: postdoctoral research associate, bioniformatics

Jasmine Donaldson: research associate

Kyle Fears: research associate

Bran McAllister: research associate

Freja Sadler: graduate student

Ant Warland: graduate student

Joe Stone: research assistant

Caroline Binda: research assistant

Gareth Edwards: research associate

Matthew Bareford: research technician

We welcome applications from prospective graduate students.  Funded studentship opportunities can be found on the University website and FindaPhD.com. We welcome a range of visiting researchers including Erasmus students.

We are currently supported by generous funding from:

CHDI https://chdifoundation.org/

MRC

LoQus23 Therapeutics

UK Dementia Research Institute

I am interested in supervising PhD students in the following areas:

  • Huntington's disease
  • neurodegeneration
  • genetic modifiers
  • short tandem repeats
  • stem cell and mouse models of disease

Current supervision

Branduff McAllister

Research student

A Warland

Anthony Warland

Research student

Ruth Jones

Miss Ruth Jones

Research student

Freja Sadler

Research student

Past projects

Recent successful PhD students:

  • Co-supervisor Ruth Jones "Targeting Microglia in Alzheimer's Disease"
  • Co-supervisor Anna Barrett “Creating Cellular Models for the Functional Characterisation of Alzheimer's Disease Risk Variants”, awarded 2018;
  • Main supervisor, Jordan Scoberg-Evans, “Examining the biological basis of deteriorating cognition in Huntington’s disease” awarded 2016;
  • Main supervisor, Kathryn Bowles, “The role of huntingtin phosphorylation in Huntington’s disease” awarded 2013;
  • Co-supervisor, Deborah Knight “Novel Schizophrenia Risk Genes and Gene Expression” awarded 2012;
  • Co-supervisor, Amy Gerrish “Analysis of Dysbindin Interacting Genes in the Pathogenesis of Schizophrenia” awarded 2010;
  • Main supervisor, Alexander Richards “Investigating the correlation of brain gene expression using microarray data” awarded 2010.