Jones, Lesley - Cardiff University

个人简介

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.

研究领域

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.

近期论文

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Bowles, K.et al. 2017. SMAD transcription factors are altered in cell models of HD and regulate HTT expression. Cellular Signalling 31, pp. 1-14. (10.1016/j.cellsig.2016.12.005) pdf Jones, L., Houlden, H. and Tabrizi, S. J. 2017. DNA repair in the trinucleotide repeat disorders. The Lancet Neurology 16(1), pp. 88-96. (10.1016/S1474-4422(16)30350-7) pdf Sims, R.et al. 2017. Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics pdf Morgan, A.et al. 2016. The correlation between inflammatory biomarkers and polygenic risk score in Alzheimer's Disease. Journal of Alzheimer's Disease (10.3233/JAD-160889) pdf Bowles, K.et al. 2016. Correction: Huntingtin Subcellular localisation is regulated by kinase signalling activity in the StHdhQ111 model of HD. PLoS ONE 11(10), article number: e0165069. (10.1371/journal.pone.0165069) pdf Precious, S.et al. 2016. FoxP1 marks medium spiny neurons from precursors to maturity and is required for their differentiation. Experimental Neurology 282, pp. 9-18. (10.1016/j.expneurol.2016.05.002) pdf Thomas, R.et al. 2016. Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: implications for Alzheimer's disease. BMC Neuroscience 17(50) (10.1186/s12868-016-0288-1) pdf Bettencourt, C.et al. 2016. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Annals of Neurology 79(6), pp. 983-990. (10.1002/ana.24656) pdf Bayram-Weston, Z.et al. 2016. Comparison of mHTT antibodies in Huntington's disease mouse models reveal specific binding profiles and steady-state ubiquitin levels with disease development.. PloS One (10.1371/journal.pone.0155834) pdf Miller, J.et al. 2016. RNA-Seq of Huntington's Disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation. Human Molecular Genetics (10.1093/hmg/ddw142) pdf