Simon Topp
A5080452479- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Neurological diseases and metabolism
- Advanced MRI Techniques and Applications
- Parkinson's Disease Mechanisms and Treatments
- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- Metabolism and Genetic Disorders
- Genetic Neurodegenerative Diseases
- Genetics and Neurodevelopmental Disorders
- Genetic Associations and Epidemiology
- Alzheimer's disease research and treatments
- NMR spectroscopy and applications
- Algorithms and Data Compression
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
- Hereditary Neurological Disorders
- biodegradable polymer synthesis and properties
- Fibromyalgia and Chronic Fatigue Syndrome Research
- semigroups and automata theory
- Electron Spin Resonance Studies
- Genomic variations and chromosomal abnormalities
- Ion Transport and Channel Regulation
- Diet and metabolism studies
- Urban, Neighborhood, and Segregation Studies
King's College London
2015-2024
UK Dementia Research Institute
2017-2023
University of North Carolina at Chapel Hill
2022
York University
2021
Medical Research Council
2016
Neuroscience Institute
2016
Kings Health Partners
2012-2014
GlaxoSmithKline (United Kingdom)
2001-2012
Age UK
2012
GlaxoSmithKline (India)
2012
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of moderate-scale sequencing study aimed at increasing number genes known to contribute predisposition for ALS. performed whole-exome 2869 ALS patients and 6405 controls. Several were found be associated, TBK1 (the gene encoding TANK-binding kinase 1) was identified as an gene. bind phosphorylate proteins involved in innate immunity autophagy, including optineurin...
Rare genetic variants contribute to complex disease risk; however, the abundance of rare in human populations remains unknown. We explored this spectrum variation by sequencing 202 genes encoding drug targets 14,002 individuals. find are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, variant catalogs will be largely incomplete. used observed patterns estimate population growth parameters, proportion a given frequency class putatively...
Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of TDP-43 is a major component, characteristic pathological feature most ALS FTD patients. Here we use genome-wide linkage analysis large ALS/FTD kindred to identify novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified CCNF missense mutation...
Capsaicin, resiniferatoxin, protons or heat have been shown to activate an ion channel, termed the rat vanilloid receptor-1 (rVR1), originally isolated by expression cloning for a capsaicin sensitive phenotype. Here we describe of human (hVR1) cDNA containing 2517 bp open reading frame that encodes protein with 92% homology receptor-1. Oocytes mammalian cells expressing this respond capsaicin, pH and temperature generating inward membrane currents. Mammalian transfected VR1 increase in...
Abstract Spiral‐based k ‐space trajectories were applied in a spectroscopic imaging sequence with time‐varying readout gradients to collect volumetric chemical shift information. In addition of low signal‐to‐noise ratio (SNR) brain metabolites, the spiral used rapidly reference signals from high SNR water signal automatically phase spectra and aid reconstruction metabolite maps. Spectral‐spatial pulses for excitation suppression. The designed achieve stable profiles presence up 20% variation...
Mutations in the gene encoding profilin 1 (PFN1) have recently been shown to cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We sequenced PFN1 cohort of ALS patients (n = 485) and detected 2 novel variants (A20T Q139L), as well 4 cases with previously identified E117G rare variant (∼ 1.2%). A case-control meta-analysis all published ALS+/− frontotemporal dementia including those this report was significant p 0.001, odds ratio 3.26 (95% confidence interval,...
Amyotrophic lateral sclerosis (ALS) presents with focal muscle weakness due to motor neuron degeneration that becomes generalized, leading death from respiratory failure within 3-5 years symptom onset. Despite the heterogeneity of aetiology, TDP-43 proteinopathy is a common pathological feature observed in >95% ALS and tau-negative frontotemporal dementia (FTD) cases. DNA/RNA-binding protein FTD translocates being predominantly nuclear form detergent-resistant, hyperphosphorylated aggregates...
Abstract Frontotemporal dementia and amyotrophic lateral sclerosis are clinically pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 genome-wide significant linkage in large European Australian family autosomal dominant inheritance of frontotemporal no mutation known or genes. Here we demonstrate the segregation novel missense variant CYLD (c.2155A>G, p.M719V) within region as cause this family....
Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age symptom onset less than 25 years and variable presentation.
Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet this complexity. Complete loss function ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition nuclear localization, protein unexpectedly localizes motor axons. The cytosolic version abolishes axonal defects, rescuing key transcripts, restores motility in paralyzed sfpq null mutants, indicating non-nuclear role...
Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and predicted cause disease through haploinsufficiency; however, many other mutations missense with unknown functional effects. We exome sequenced 699 familial sclerosis patients identified 16 novel or extremely rare protein-changing variants. characterized a subset of these: p.G217R, p.R357X, p.C471Y. Here, we show that the p.R357X p.G217R both abolish ability...
<h3>Importance</h3> Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with poor prognosis and median survival of 3 years. However, significant proportion patients survive more than 10 years from symptom onset. <h3>Objective</h3> To identify gene variants influencing in ALS. <h3>Design, Setting, Participants</h3> This genome-wide association study (GWAS) analyzed data sets several European countries the United States that were collected by Italian...
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...
Abstract Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people SOD1 -ALS ALS no recorded variant. We investigate age at symptom onset time from to death censoring using Cox proportional-hazards regression. The dataset reports for 1122...