Johnathan Cooper‐Knock
A5042136207- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Neurological diseases and metabolism
- Parkinson's Disease Mechanisms and Treatments
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Cancer-related gene regulation
- RNA regulation and disease
- Genetic Associations and Epidemiology
- Mitochondrial Function and Pathology
- Retinal Diseases and Treatments
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Cholinesterase and Neurodegenerative Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Hereditary Neurological Disorders
- Ubiquitin and proteasome pathways
- Glaucoma and retinal disorders
- Ion channel regulation and function
- Pulmonary Hypertension Research and Treatments
- Bioinformatics and Genomic Networks
- Cancer-related molecular mechanisms research
- Genetics and Neurodevelopmental Disorders
University of Sheffield
2016-2025
Neuroscience Institute
2025
Royal Hallamshire Hospital
2012-2024
Azienda Ospedaliero-Universitaria Cagliari
2024
University of Cagliari
2018-2024
Hong Kong University of Science and Technology
2023
University of Hong Kong
2023
UK Dementia Research Institute
2023
University College London
2013-2023
National Hospital for Neurology and Neurosurgery
2023
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...
Objective To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods Linkage disequilibrium score regression Mendelian randomization were applied a large‐scale, data‐driven manner to explore genetic correlations relationships between >700 phenotypic traits ALS. Exposures consisted of publicly available genome‐wide association studies (GWASes) summary statistics from MR Base LD‐hub . The outcome data came the recently published ALS GWAS...
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes...
Background Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case–control statistical evidence implicating oligogenicity with disease or clinical outcomes is limited. Considering its direct and therapeutic implications, we aim to perform large-scale robust investigation of ALS the course. Methods We leveraged Project MinE genome sequencing datasets (6711 cases 2391 controls) identify associations between known genes risk, as well...
ABSTRACT C9orf72-related amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) has proven difficult to model in mice. Liu et al. (2016) reported a bacterial artificial chromosome (BAC) transgenic mouse displaying behavioural, motor and pathological abnormalities. This was followed by multiple laboratories independently refuting confirming phenotypes. A proposed explanation centred on the use of different FVB background lines (from The Jackson Laboratory Janvier Labs). We studied...
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...
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 universally fatal neurodegenerative disease. ALS determined by gene-environment interactions and improved understanding of these may lead to effective personalised medicine. The role physical exercise in the development currently controversial.First, we dissected exercise-ALS relationship series two-sample Mendelian randomisation (MR) experiments. Next tested for enrichment genetic risk within exercise-associated transcriptome changes. Finally,...
Objective The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether targeted 44 ALS-relevant genes would have a significant impact on disease subclassification and care. Methods We performed 44-gene panel prospective case series 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed by specialist Consultant Neurologist. 7/100 had familial...
SARM1, a protein with critical NADase activity, is central executioner in conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles patients amyotrophic lateral sclerosis (ALS) other motor nerve disorders that alter the auto-inhibitory ARM domain and constitutively hyperactivate activity. The constitutive activity these variants similar to lacking entire greatly exceeds wild-type even presence nicotinamide mononucleotide...
Abstract There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up 60%. Both Mendelian and small effect variants have been identified, but in common other conditions, such only explain little the heritability. Genomic structural variation might account for some this otherwise unexplained We therefore investigated association between set 25 ALS genes, risk phenotype. As expected, repeat expansion C9orf72 gene was identified as...