A5052764879- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- Alzheimer's disease research and treatments
- RNA regulation and disease
- Nerve injury and regeneration
- Parkinson's Disease Mechanisms and Treatments
- Neurological diseases and metabolism
- Cholinesterase and Neurodegenerative Diseases
- Axon Guidance and Neuronal Signaling
- Bone Metabolism and Diseases
- Nuclear Structure and Function
- Toxin Mechanisms and Immunotoxins
- Cancer-related gene regulation
- Cell Adhesion Molecules Research
- Wnt/β-catenin signaling in development and cancer
- Biotin and Related Studies
- TGF-β signaling in diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Signaling Pathways in Disease
- Cancer Treatment and Pharmacology
- Pain Mechanisms and Treatments
- NF-κB Signaling Pathways
- Immune Response and Inflammation
King's College London
2018-2021
Babraham Institute
2016-2021
Cardiff University
2013-2018
Neuroscience Institute
2018
Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, relationship between these phenomena remains poorly defined. Here, we showed that recapitulates pathology by upregulating shortened (sTDP43) splice isoforms. These truncated isoforms accumulated cytoplasm formed insoluble inclusions sequestered full-length via preserved N-terminal interactions. Consistent with findings, sTDP43...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests ALS 'dying-back' disease, peripheral denervation axonal degeneration occurring before loss of neuron cell bodies. Distal to nerve injury, similar pattern can be seen, which mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha TIR motif-containing 1 (Sarm1) key...
Inappropriate aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark motor neuron disease (MND). Current methods for quantifying heterogeneous aggregate populations in biofluids are limited, precluding their routine use diagnosis and monitoring. Single molecule microscopy overcome these limitations to deliver quantitative morphological compositional fingerprinting molecular assemblies containing TDP-43. Here, we demonstrate the application such extracts from donor brain tissues. We...
APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation has been implicated in tumorigenesis autoimmune diseases. Here we report expression first known activity nervous system. one its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells fetal postnatal mice. In culture, these neurons secreted APRIL, function-blocking antibodies to either or reduced...
Dendrite size and morphology are key determinants of the functional properties neurons. Here, we show that growth differentiation factor 5 (GDF5), a member bone morphogenetic protein (BMP) subclass transforming β superfamily with well-characterised role in limb morphogenesis, is regulator elaboration pyramidal cell dendrites developing hippocampus. Pyramidal cells co-express GDF5 its preferred receptors, BMP receptor 1B 2, during development. In culture, substantially increased dendrite, but...
Abstract Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes advance of symptom onset. Recapitulating these preclinical models would help to improve our understanding the molecular causes underlying regionally selective atrophy early disease. We therefore investigated translational potential TDP-43Q331K knock-in mouse model amyotrophic sclerosis-frontotemporal using MRI. performed vivo mice. Regions significant...
TWE-PRIL is a naturally-occurring fusion protein of components two TNF superfamily members: the extracellular domain APRIL and intracellular transmembrane domains TWEAK with no known function. Here we show that April−/− mice (which lack TWE-PRIL) exhibited overgrowth sympathetic fibers in vivo, neurons cultured from these had significantly longer axons than wild type littermates. Enhanced axon growth was prevented by expressing full-length but not treating them soluble APRIL. Soluble APRIL,...
Abstract Perseveration and apathy are two of the most common behavioural psychological symptoms dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal (ALS–FTD). Availability a validated behaviourally characterised animal model is crucial for translational research into BPSD FTD context. We evaluated male TDP-43 Q331K mouse, an ALS–FTD with human-equivalent mutation (TDP-43 ) knocked endogenous Tardbp gene. utilised panel tasks delivered using rodent touchscreen apparatus,...
Defects in the mRNA export scaffold protein GANP, encoded by MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here phenotypic range associated variants, describing a severely hypotonic child and sibling pair progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals seven unrelated families indicates that disease variants result depletion GANP except when they alter...
Abstract Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly-conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, relationship between these phenomena remains poorly defined. Here, we showed that recapitulates pathology by upregulating shortened (s) splice isoforms. These truncated isoforms accumulated cytoplasm formed insoluble inclusions sequestered full-length via preserved N-terminal interactions. Consistent with findings, sTDP43...
Abstract Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a progressive and ultimately fatal disease spectrum characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current modifying drugs have modest effects novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential GSK3 inhibition to ameliorate TDP43-mediated...
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that increasingly understood to have long prodromal periods. Investigation of these early stages promises yield valuable biomarkers disease will be key understanding mechanisms underlying the genesis ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology computed tomography identify structural cellular readouts stage TDP-43 Q331K knock-in mouse model...
SUMMARY Loss-of-function of the mRNA export protein GANP ( MCM3AP gene) cause early-onset sensorimotor neuropathy, characterised by axonal degeneration in long peripheral nerves. functions as a scaffold at nuclear pore complexes, contributing to selective mRNAs. Here, we aimed identify motor neuron specific transcripts that are regulated and may be limiting for local synthesis axons. We compared neurons with gene edited mutation Sac3 binding domain isogenic controls. also examined...