A5080478575- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Neurological diseases and metabolism
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Genetic Neurodegenerative Diseases
- biodegradable polymer synthesis and properties
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Hereditary Neurological Disorders
- Synthetic Organic Chemistry Methods
- Cancer-related gene regulation
- Oral and Maxillofacial Pathology
- Complementary and Alternative Medicine Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- Mitochondrial Function and Pathology
- RNA regulation and disease
- Histone Deacetylase Inhibitors Research
- Cholinesterase and Neurodegenerative Diseases
- Bioinformatics and Genomic Networks
- Cerebrovascular and genetic disorders
- Iron Metabolism and Disorders
- Dementia and Cognitive Impairment Research
- Multiple Sclerosis Research Studies
- Genomics, phytochemicals, and oxidative stress
University of Sheffield
2016-2025
Right to Care
2022
Neuroscience Institute
2018
King's College London
2018
St Bernard's Hospital
2014
Jenner Institute
2013
Sheffield Children's NHS Foundation Trust
2013
Cardiff University
2013
University College London
2013
Sheffield Children's Hospital
2008
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with large proportion cases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).We screened 4448 patients diagnosed ALS (El Escorial criteria) 1425 FTD (Lund-Manchester from 17 regions worldwide for GGGGCC using repeat-primed PCR assay. assessed familial disease status on basis self-reported family history similar neurodegenerative diseases at time sample...
Abstract Objective Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality superoxide dismutase ‐ 1 ( SOD1 ) mutations. Most research in past decade has focused on neurotoxicity mutant SOD1, this knowledge directed therapeutic strategies. We recently identified TDP‐43 as major pathological protein sporadic ALS. In study, we investigated larger series...
Objective An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism neurodegeneration unknown, but a direct effect on RNA processing mediated by foci transcribed from repeat sequence has been proposed. Methods Gene expression profiling utilised total extracted motor neurons lymphoblastoid cell lines derived human ALS patients, including those with an C9ORF72, controls. In lines, length...
Intronic expansion of the GGGGCC hexanucleotide repeat within C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial sporadic cases. Initial reports indicate that this variant dementia/amyotrophic sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The phenotype not yet well characterized. We report clinical pathological phenotypes pathogenic mutations a cohort 563 cases from...
GGGGCC repeat expansions of C9orf72 represent the most common genetic variant amyotrophic lateral sclerosis and frontotemporal degeneration, but mechanism pathogenesis is unclear. Recent reports have suggested that transcribed might form toxic RNA foci sequester various processing proteins. Consensus as to identity binding partners missing whole neuronal proteome investigation needed. Using fluorescence in situ hybridization we first identified nuclear cytoplasmic peripheral central nervous...
Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation CHMP2B was recently identified Danish pedigree autosomal dominant FTD. Subsequently, two unrelated patients familial ALS, one whom also showed features FTD, were shown to carry missense mutations CHMP2B. The initial aim this study determine whether contribute more broadly ALS pathogenesis.Sequencing 433 cases from the North...
The cellular pathways of motor neuronal injury have been investigated in the SOD1 G93A murine model familial amyotrophic lateral sclerosis (ALS) using laser-capture microdissection and microarray analysis. advantages this study include following: analysis changes specifically neurons (MNs), while still detecting effects interactions with neighboring cells; ability to profile during disease progression, an approach not possible human ALS; use transgenic mice bred on a homogeneous genetic...
Familial amyotrophic lateral sclerosis (FALS) is caused, in 20% of cases, by mutations the Cu/Zn superoxide dismutase gene (SOD1). Although motor neuron injury occurs through a toxic gain function, precise mechanism(s) remains unclear. Using an established NSC34 cellular model for SOD1-associated FALS, we investigated effects mutant SOD1 specifically cells modelling vulnerable cell population, neurons, without contamination from non-neuronal present CNS. expression profiling, 268 transcripts...
Amyotrophic lateral sclerosis is a neurodegenerative disease in which death of motoneurons leads to progressive failure the neuromuscular system resulting frequently within 2–3 years symptom onset. Focal onset and propagation symptoms contiguous motoneuron groups striking feature human progression. Recent work, using mutant superoxide dismutase 1 murine models vitro culture systems has indicated that astrocytes are likely contribute injury However, basis this astrocyte toxicity and/or...
GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We others have proposed that RNA transcribed from sequence is toxic via sequestration RNA-binding factors. Both GGGGCC-repeat (sense) CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as foci, but their relative expression pattern within CNS contribution to disease has not been determined. Blinded examination...
A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing eye movements and function external sphincters, with corresponding preservation motor neurons in brainstem oculomotor nuclei, Onuf's nucleus sacral spinal cord. Studying differences properties that are vulnerable resistant to disease process ALS may provide insights into mechanisms neuronal degeneration, identify targets for therapeutic manipulation. We used microarray analysis determine gene expression...
Mutations in the RNA binding protein fused sarcoma/translated liposarcoma (FUS/TLS) cause amyotrophic lateral sclerosis (ALS). Although ALS-linked mutations FUS often lead to a cytosolic mislocalization of protein, pathogenic mechanisms underlying these remain poorly understood. To gain insight into mechanisms, we examined biochemical, cell biological and functional properties mutant neurons. Expression different mutants (R521C, R521H, P525L) neurons caused axonal defects. A interaction...
To determine the frequency of and clinicopathologic phenotypes associated with FUS/TLS mutations in a large cohort amyotrophic lateral sclerosis (ALS) cases from north England.Genetic screening project neuropathologic examination postmortem tissue selected cases. The clinical details are also presented.Neurology departments 2 university teaching hospitals England.The 15 exons were sequenced an initial 42 familial ALS (FALS) 117 sporadic (SALS) Exons 14 subsequently screened larger 431 SALS...
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative condition characterized by loss of motor neurones and progressive muscle wasting. There no diagnostic test for ALS therefore robust biomarkers would not only be valuable diagnosis, but also the classification disease subtypes, monitoring responses to drugs tracking progression. As regulators gene expression, microRNAs (miRNAs) are increasingly used prognostic purposes in various states with increasing exploration disorders. We...
Abstract Hexanucleotide repeat expansions in the C9ORF72 gene are commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression transcripts dipeptide proteins trigger multiple mechanisms neurotoxicity. How get exported from nucleus is unknown. Here, we show that depletion nuclear export adaptor SRSF1 prevents neurodegeneration locomotor deficits a Drosophila model C9ORF72-related disease. This intervention suppresses cell death patient-derived motor...
Aims Loss of nuclear TDP ‐43 characterizes sporadic and most familial forms amyotrophic lateral sclerosis ( ALS ). (encoded by TARDBP ) has multiple roles in RNA processing. We aimed to determine whether (1) splicing dysregulation is present lower motor neurones a neurone‐like cell model; (2) mutations (mt are associated with aberrant using patient‐derived fibroblasts. Methods A ffymetrix exon arrays were used study mRNA expression obtained laser capture microdissection autopsy tissue from...
Amyotrophic lateral sclerosis (ALS) is a clinical subtype of motor neurone disease (MND), fatal neurodegenerative involving the loss both upper and lower neurones from cortex, brainstem, spinal cord. Identifying specific biomarkers would help to not only improve diagnostic delay but also classify subtypes, monitor response therapeutic drugs track progression. miRNAs are small non-coding RNA responsible for regulating gene expression ultimately protein have been used as many cancers...