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Yr Athro Lesley Jones

Yr Athro Lesley Jones

Professor, Division of Psychological Medicine and Clinical Neurosciences

Yr Ysgol Meddygaeth

Email
jonesl1@cardiff.ac.uk
Telephone
+44 (0)29 2068 8469
Campuses
2.53, Adeilad Hadyn Ellis, Heol Maendy, Caerdydd, CF24 4HQ
Users
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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.

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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 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 ( 4 ) 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 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 (5).