Lesley Jones
A5065920088- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Alzheimer's disease research and treatments
- Bioinformatics and Genomic Networks
- Neurological disorders and treatments
- Genetic Associations and Epidemiology
- RNA Research and Splicing
- Fungal and yeast genetics research
- DNA Repair Mechanisms
- Muscle Physiology and Disorders
- Parkinson's Disease Mechanisms and Treatments
- Genetics and Neurodevelopmental Disorders
- Neuroscience and Neuropharmacology Research
- Computational Drug Discovery Methods
- 14-3-3 protein interactions
- Neuroinflammation and Neurodegeneration Mechanisms
- Ubiquitin and proteasome pathways
- Genomics and Rare Diseases
- Dementia and Cognitive Impairment Research
- CRISPR and Genetic Engineering
- Adipose Tissue and Metabolism
- Neurotransmitter Receptor Influence on Behavior
- Nutrition, Genetics, and Disease
- Pluripotent Stem Cells Research
- Cholesterol and Lipid Metabolism
Cardiff University
2015-2024
Medical Research Council
2013-2023
Dudley Group NHS Foundation Trust
2022
UK Dementia Research Institute
2019-2022
Universität Ulm
2020-2021
Harvard University
2021
Massachusetts General Hospital
2021
Framingham Heart Study
2018
Boston University
2018
Institute for Neurodegenerative Disorders
2018
Background Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought identify new genes, using an alternative gene-wide analytical approach tests patterns of association within in the powerful genome-wide dataset International Genomics Project Consortium, comprising over 7 m genotypes from 25,580 cases and 48,466 controls. Principal Findings In addition...
Huntington's disease (HD) pathology is well understood at a histological level but comprehensive molecular analysis of the effect in human brain has not previously been available. To elucidate phenotype HD on genome-wide scale, we compared mRNA profiles from 44 brains with those 36 unaffected controls using microarray analysis. Four regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor 4 (BA4)]. The greatest number magnitude...
The transcription factor REST silences neuronal gene expression in non-neuronal cells. In neurons, the protein is sequestered cytoplasm part through binding to huntingtin. Polyglutamine expansions huntingtin, which causes Huntington's disease (HD), abrogates REST-huntingtin binding. Consequently, translocates nucleus, occupies RE1 repressor sequences and decreases expression. this work, we found that levels of several microRNAs (miRNAs) with upstream sites are decreased HD patient cortices...
Background Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified first strongly supported LOAD susceptibility genes since discovery involvement APOE in early 1990s. We have now exploited these GWAS datasets to uncover key pathophysiological processes. Methodology applied a recently developed tool for mining data biologically meaningful information dataset. The principal findings were then tested an independent...
The identification of subjects at high risk for Alzheimer's disease is important prognosis and early intervention. We investigated the polygenic architecture accuracy prediction models, including excluding component in model. This study used genotype data from powerful dataset comprising 17 008 cases 37 154 controls obtained International Genomics Project (IGAP). Polygenic score analysis tested whether alleles identified to associate with one sample set were significantly enriched relative...
To test the hypotheses that mutant huntingtin protein length and wild-type dosage have important effects on disease-related transcriptional dysfunction, we compared changes in mRNA seven genetic mouse models of Huntington's disease (HD) postmortem human HD caudate. Transgenic expressing short N-terminal fragments (R6/1 R6/2 mice) exhibited most rapid gene expression, consistent with previous studies. Although brains knock-in full-length transgenic took longer to appear, 15- 22-month...
The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They caused by expanded CAG tracts, encoding glutamine, in different genes. Longer repeat tracts associated with earlier ages at onset, but this does not account for all of difference, existence additional genetic modifying factors has been suggested these A recent genome-wide association study (GWAS) HD found between age...
Abstract Background Late‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Project (IGAP). To identify biology underlying disease, we extended these genetic data a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used IGAP to associated functional pathways correlated gene expression networks human brain. Results identified an excess curated biological enrichment association. Enriched areas included immune...
The apolipoprotein E ( APOE ) gene is the only genetic risk factor that has so far been linked to for late-onset Alzheimer's disease (LOAD). However, 50 percent of cases do not carry an APOE4 allele, suggesting other factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD detect susceptibility loci. Here we report evidence locus on chromosome 10. Our stage one multipoint lod score (logarithm odds ratio linkage/no linkage) 2.48 (266 pairs) increased 3.83 2...
Many pathways have been proposed as contributing to Huntington's disease (HD) pathogenesis, but generally the in vivo effects of their perturbation not compared with reference data from human patients. Here we examine how accurately mechanistically motivated and genetic HD models recapitulate striatal gene expression phenotype HD. The representative model was R6/2 transgenic mouse, which expresses a fragment huntingtin protein containing long CAG repeat. Pathogenic mechanisms examined...
Abstract We performed a two‐stage genome screen to search for novel risk factors late‐onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In second stage, we genotyped 451 (ASPs) with an additional 91 markers, in 16 regions where multipoint LOD score was greater than 1 I. Ten maintained scores excess of II, on chromosomes (peak B), 5, 6, 9 (peaks A and 10, 12, 19, 21, X....
One of the characteristic manifestations several neurodegenerative diseases is progressive decline in cognitive ability. In order to determine suitability six mouse strains (129S2/Sv, BALB/c, C3H/He, C57BL/6j, CBA/Ca and DBA/2) as transgenic background strains, we investigated performance on a variety tasks designed identify subtle changes cognition. addition, test exploratory behaviour was used probe level underlying anxiety these can be confounding factor behavioural generally. The C3H/He...
Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted somatic of, and polymorphisms within, HTT glutamine-encoding repeat, DNA repair genes.The sequence of proportion CAG expansions in blood from participants inheriting 40 to 50 repeats within TRACK-HD Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene genotyped kompetitive...
Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within polymorphic 9 bp tandem in MSH3/DHFR, variant most significantly associated with progression disease. Using Illumina sequencing 1 subjects, we show that rs557874766 is alignment artefact, minor allele for...
Huntington's disease (HD) is an inherited neurodegenerative caused by expanded CAG repeat in the huntingtin (HTT) gene. length explains around half of variation age at onset (AAO) but genetic elsewhere genome accounts for a significant proportion remainder. Genome-wide association studies have identified bidirectional signal on chromosome 15, likely underlain FANCD2- and FANCI-associated nuclease 1 (FAN1), involved DNA interstrand cross link repair. Here we show that increased FAN1...
We previously demonstrated that sodium butyrate is neuroprotective in Huntington's disease (HD) mice and this therapeutic effect associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show enhancing MKP-1 sufficient to achieve neuroprotection lentiviral models HD. Wild-type overexpression inhibited apoptosis primary striatal neurons exposed an N-terminal fragment polyglutamine-expanded huntingtin (Htt171–82Q), blocking...
Huntington's disease (HD) is a dominantly inherited neurodegenerative caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely the size HTT repeat. However, emerging evidence strongly supports role for other genetic factors modifying pathogenesis driven mutant huntingtin. A recent genome-wide association analysis to discover modifiers provided initial modifier loci on chromosomes 8 and 15 suggestive locus chromosome 3....