A5005749877- 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
- Cancer-related gene regulation
- Ion channel regulation and function
- interferon and immune responses
- Mitochondrial Function and Pathology
- CRISPR and Genetic Engineering
- Alzheimer's disease research and treatments
- RNA regulation and disease
- Ubiquitin and proteasome pathways
- SARS-CoV-2 and COVID-19 Research
- Cellular transport and secretion
- Cancer Genomics and Diagnostics
- Glycogen Storage Diseases and Myoclonus
- Lysosomal Storage Disorders Research
- Nerve injury and regeneration
- Metabolism and Genetic Disorders
- Amino Acid Enzymes and Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Cholinesterase and Neurodegenerative Diseases
- Viral Infections and Immunology Research
University of Sheffield
2018-2025
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...
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,...
TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may extrinsic stressors as "second hit." undergoes reversible nuclear condensation stressed cells including neurons. Here, we demonstrate that stress-inducible condensates are RNA-depleted, non-liquid assemblies distinct from the known bodies. Their formation requires oligomerization ATP inhibited by RNA. Using confocal nanoscanning assay, find amyotrophic lateral sclerosis...
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C GLT8D1, which co-segregate with disease. Sequencing of local international cohorts demonstrated significant...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function an upstream driver or downstream modifier neurotoxicity. We separated genetic determinants function, including variation within the genome autosomes; from changeable factors DNA copy number (mtCN). Across three cohorts 6,437 ALS patients, we discovered that set haplotypes, chosen because they are...
Abstract Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity develop sensitive and biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we performed whole genome bisulfite sequencing (WGBS) iPSC-derived neurologically normal individuals. By comparing methylation with atlas tissue derived MN-specific signature...
Abstract Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length of 31-33 CAG-repeats is sporadic ALS full ≥34 SCA2. We report the clinical phenotype -positive patients their relatives, identified three specialist clinics, which force reconsideration this dichotomy. also frequency...
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling neuronal survival, overexpression of ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion risk variants within the non-coding genome, but further characterization has been limited by lack appropriate tools. By designing applying pipeline to identify pathogenic genetic variation enhancer...
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by the selective progressive death of motor neurons (MNs). Understanding genetic molecular factors influencing ALS survival crucial for management therapeutics. In this study, we introduce deep learning-powered analysis framework to link rare noncoding variants survival. Using data from human induced pluripotent stem cell (iPSC)-derived MNs, method prioritizes functional using learning, links...
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders viewed as clinically distinct ALS resulting from 30-33 CAG-repeats SCA2 >34 CAG-repeats. We describe 67-year old 32 who presented simultaneous symptoms SCA2. Our case demonstrates that clinical dichotomy between ATXN2-ALS is false. suggest instead length...
Abstract Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic unknown majority cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as serum concentration specific metabolite, and risk. We obtained genome-wide association study summary statistics for concentrations 566 metabolites which were population matched with sclerosis. For each we performed...
(Cell Reports 33, 108456-1–108456-8.e1–e5; December 1, 2020) In the originally published version of this article, Eran Elhaik was incorrectly spelled in author list. The corrected list appears here and with article online. authors regret error. Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk GeneCooper-Knock et al.Cell ReportsDecember 01, 2020In BriefCooper-Knock al. identify amyotrophic lateral sclerosis (ALS) risk variants non-coding regulatory DNA linked to a...
Abstract We describe an autosomal dominant, multi‐generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co‐segregates with a heterozygous p.Y374X nonsense mutation within TDP‐43. Mislocalization of TDP‐43 and formation insoluble TDP‐43‐positive neuronal cytoplasmic inclusions is the hallmark pathology >95% ALS patients. Neuropathological examination single case for CNS tissue was available indicated typical lower motor neurons, but classical were absent from cortex....
Amyotrophic lateral sclerosis (ALS) is an invariably fatal adult-onset neurodegenerative disorder; approximately 10% of ALS monogenic but all exhibits significant heritability. The skeletal muscle sodium channelopathies are a group inherited, non-dystrophic ion channel disorders caused by heterozygous point mutations in the SCN4A gene, leading to clinical manifestations congenital myotonia, paramyotonia, and periodic paralysis syndromes. We provide genetic evidence concurrence these two rare...
New therapeutic targets are a valuable resource for treatment of SARS-CoV-2 viral infection. Genome-wide association studies have identified risk loci associated with COVID-19, but many comorbidities and not specific to host–virus interactions. Here, we identify experimentally validate link between reduced expression EXOSC2 replication. was one the 332 host proteins examined, all which interact directly proteins. Aggregating COVID-19 genome-wide statistics gene-specific eQTLs revealed an...
ABSTRACT Background 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. Methods We dissected exercise-ALS relationship series two-sample Mendelian randomisation (MR) experiments. then we tested for enrichment genetic risk within exercise-associated transcriptome...
Abstract Mutations within GLT8D1 contribute to familial amyotrophic lateral sclerosis. Pathogenic mutations impair glycosyltransferase enzymatic function via a dominant negative mechanism, yet the downstream mechanism leading neurotoxicity is unclear. Here we show that p.R92C mutation causes fragmentation of Golgi network and reduces ganglioside expression membrane lipid rafts (MLRs), impaired neurotrophin signalling. Expression p.R92C-GLT8D1 in HEK293 cells mouse primary neurons GM1...
<title>Abstract</title> Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in <italic>ATXN2</italic> TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length of 31–33 CAG-repeats is sporadic ALS full ≧ 34 SCA2. We report the clinical phenotype <italic>ATXN2</italic>-positive patients their relatives, identified three specialist clinics, which...
<title>Abstract</title> Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity develop sensitive and biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we performed whole genome bisulfite sequencing (WGBS) iPSC-derived neurologically normal individuals. By comparing methylation with atlas tissue derived MN-specific...