A5044940489- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Scientific Computing and Data Management
- Mitochondrial Function and Pathology
- Prion Diseases and Protein Misfolding
- Distributed and Parallel Computing Systems
- Neurological diseases and metabolism
- Genomics and Phylogenetic Studies
- Genetic Neurodegenerative Diseases
- Parkinson's Disease Mechanisms and Treatments
- Pluripotent Stem Cells Research
- Cancer-related gene regulation
- Neuroinflammation and Neurodegeneration Mechanisms
- Cholinesterase and Neurodegenerative Diseases
- CRISPR and Genetic Engineering
- Neural dynamics and brain function
- Neurogenesis and neuroplasticity mechanisms
- Intracerebral and Subarachnoid Hemorrhage Research
- Infective Endocarditis Diagnosis and Management
- RNA regulation and disease
- Genetics, Bioinformatics, and Biomedical Research
- Muscle and Compartmental Disorders
- Peripheral Neuropathies and Disorders
- Genomics and Rare Diseases
- RNA Research and Splicing
University of Oxford
2010-2025
John Radcliffe Hospital
2008-2024
MRC Weatherall Institute of Molecular Medicine
2019
An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is major cause amyotrophic lateral sclerosis (ALS), accounting for up to 40% familial cases and 7% sporadic ALS European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts patients carrying expansions, differentiated these functional motor cortical neurons, performed an extensive phenotypic characterization. In iPSC-derived decreased cell survival correlated with dysfunction Ca(2+)...
A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is most common cause amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, precise molecular mechanism by which directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease arising due to interaction C9ORF72 with RAB7L1 GTPase regulate vesicle trafficking. Endogenous between was confirmed human SH-SY5Y neuroblastoma cells. The led haploinsufficiency resulting severely...
TDP-43 dysfunction is common to 97% of amyotrophic lateral sclerosis (ALS) cases, including those with mutations in C9orf72. To investigate how C9ORF72 drive cellular pathology ALS and identify convergent mechanisms between TARDBP mutations, we analyzed motor neurons (MNs) derived from induced pluripotent stem cells (iPSCs) patients ALS. iPSC-MNs have higher Ca2+ release after depolarization, delayed recovery baseline glutamate stimulation, lower levels calbindin compared CRISPR/Cas9...
Abstract The routine clinical integration of individualized objective markers disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise leading candidate biofluid biomarkers stratification and potential assessment sclerosis. Incident patients (n = 258), other neurological diseases 80) healthy control...
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant hexanucleotide repeat expansion (HRE) mutation in C9orf72 . Here, we study its consequences for microglial function using human iPSC-derived By RNA-sequencing, identify enrichment pathways associated immune cell activation and...
Abstract The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting region, with risk creating indels genomic instability. In this study, we demonstrate complete correction an induced pluripotent stem cell (iPSC) line derived...
Our objective was to establish the pattern of spread in lower limb-onset ALS (contra- versus ipsi-lateral) and its contribution prognosis within a multivariate model. Pattern established 109 sporadic patients with limb-onset, prospectively recorded Oxford Sheffield tertiary clinics from 2001 2008. Survival analysis by univariate Kaplan-Meier log-rank Cox proportional hazards. Variables studied were time next limb progression, site age at symptom onset, gender, diagnostic latency use...
We present a series of 19 cases invasive Group A streptococcal (iGAS) infection reported to the Thames Valley Health Protection Unit from 1 December 2010 15 January 2011. Ten patients died and prodrome influenza-like illness was in 14 cases.Influenza B co-infection confirmed four cases,three which were fatal. Our report provides further evidence that influenza with iGAS has potential cause significant morbidity mortality.
Abstract Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor degeneration with additional involvement of non-neuronal cells, in particular, microglia. In previous work, we have established protocols for the differentiation iPSC-derived spinal neurons and Here, combine both cell lineages establish a novel co-culture microglia, which is compatible identity function. Co-cultured microglia express key markers transcriptomically resemble primary human...
Abstract Background Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions spinal motor neurons glial cells is characteristic amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology common sporadic ALS familial without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether abnormalities occur in non-ALS forms neuron disease. Here, we characterise localisation,...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the corticomotorneuronal network responsible for voluntary movement. There are well-established clinical, genetic and pathological overlaps between ALS frontotemporal dementia (FTD), which together constitute 'TDP-43 proteinopathies'. An ever-expanding list genes in mutation leads to typical have implicated abnormalities RNA processing, protein homoeostasis axonal transport. How these apparently distinct...
Abstract The mammalian neocortex is characterized by a variety of neuronal cell types and precise arrangements synaptic connections, but the processes that generate this diversity are poorly understood. Here we examine how pool embryonic progenitor cells consisting apical intermediate progenitors (aIPs) contribute to within upper layers mouse cortex. In utero labeling combined with single-cell RNA-sequencing reveals aIPs can transcriptionally defined glutamatergic types, when compared...
Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect biology underlying cell-specific vulnerability ALS is uncertain. We therefore compared phenotypes due to HRE in MNs sensory (SNs), are relatively spared ALS. The iPSC models were able partially reproduce differential gene expression seen between...
<ns4:p>In the genomics era computational biologists regularly need to process, analyse and integrate large complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in pipelines or workflows, often with several branches. Large data volumes mean that processing needs be quick efficient scientific rigour requires analysis consistent fully reproducible. We have developed CGAT-core, a python package for rapid construction of workflows. CGAT-core seamlessly...
<ns4:p>In the genomics era computational biologists regularly need to process, analyse and integrate large complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in pipelines or workflows, often with several branches. Large data volumes mean that processing needs be quick efficient scientific rigour requires analysis consistent fully reproducible. We have developed CGAT-core, a python package for rapid construction of workflows. CGAT-core seamlessly...
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature ALS cytoplasmic mislocalization aggregation TDP-43 in affected neurons, which found 97% cases. Recent reports have shown that mitochondrial dysfunction plays significant role neuron degeneration ALS, modulates several transcripts. In this study, we used induced pluripotent stem cell-derived neurons...
The identification of blood-based biomarkers specific to the diagnosis amyotrophic lateral sclerosis (ALS) is an active field academic and clinical research. While inheritance studies have advanced field, a majority patients do not known genetic link disease, making direct sequence-based testing for ALS difficult. ability detect biofluid-based epigenetic changes in would expand relevance using genomic information disease diagnosis.
Abstract Background Myositis is a recognised complication of numerous systemic viral infections including influenza. In adults the typical pattern characterised by myalgia and marked proximal muscle weakness in upper lower limbs resolves slowly over weeks rather than days. Case presentation Here, we describe two male patients with myositis an unusual distribution distal limbs, which both followed flu-like illness resolved spontaneously. Both had moderate elevations creatine kinase, extensive...