A5080031354- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- Pluripotent Stem Cells Research
- Heat shock proteins research
- Parkinson's Disease Mechanisms and Treatments
- Endoplasmic Reticulum Stress and Disease
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Genetic Neurodegenerative Diseases
- S100 Proteins and Annexins
- Protein Structure and Dynamics
- RNA Research and Splicing
- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Muscle Physiology and Disorders
University of York
2019-2021
King's College London
2014-2019
UK Dementia Research Institute
2017
Hammersmith Hospital
2010-2012
Imperial College London
2007-2012
Charing Cross Hospital
2007
TARDBP (TDP-43) is the major pathological protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Large TDP-43 aggregates decorated by degradation adaptor proteins are seen cytoplasm of remaining neurons patients post mortem. accumulation, ALS-linked mutations within pathways, implicates failed clearance as a primary disease mechanism. Here we report differential roles ubiquitin proteasome system (UPS) autophagy TDP-43. We have investigated effects UPS inhibitors on...
Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Following the mutation screening of genes known to cause amyotrophic lateral sclerosis (ALS) in index cases from 107 familial ALS (FALS) kindred, a point was identified vesicle-associated membrane protein-associated protein B (VAPB), or VAMP-associated B, causing an amino acid change threonine isoleucine at codon 46 (T46I) one FALS case but not 257 controls. This is important finding because it only second this gene that causes ALS. In order investigate pathogenic effects mutation, we have...
Detergent-resistant, ubiquitinated and hyperphosphorylated Tar DNA binding protein 43 (TDP-43, encoded by TARDBP ) neuronal cytoplasmic inclusions are the pathological hallmark in ∼95% of amyotrophic lateral sclerosis ∼60% frontotemporal lobar degeneration cases. We sought to explore role for heat shock response clearance insoluble TDP-43 a cellular model disease validate our findings transgenic mice human tissues. The is stress-responsive protective mechanism regulated transcription factor...
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...
An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation G4C2 RNA can result in five different dipeptide proteins (DPR: poly GA, GP, GR, PA, PR), which aggregate into neuronal cytoplasmic nuclear inclusions affected patients, however their contribution to disease pathogenesis remains controversial. We show that among DPR proteins,...
TDP-43 is an RNA-binding protein constituting the pathological inclusions observed in ~95% of ALS and ~50% FTD patients. In FTD, mislocalises to cytoplasm forms insoluble, hyperphosphorylated ubiquitinated aggregates that enhance cytotoxicity contribute neurodegeneration. Despite its primary role as RNA/DNA-binding protein, how deficiencies disease onset progression little understood. Among many identified familial mutations causing ALS/FTD, only two cause deficiency, K181E K263E. this...
TDP-43 is found in cytoplasmic inclusions 95% of amyotrophic lateral sclerosis (ALS) and 60% frontotemporal lobar degeneration (FTLD). Approximately 4% familial ALS caused by mutations TDP-43. The majority these are the glycine-rich domain, including variant M337V, which one most common In order to investigate use allele-specific RNA interference (RNAi) as a potential therapeutic tool, we designed screened set siRNAs that specifically target TDP-43M337V mutation. Two siRNA silenced M337V...
Background The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [1,2]. mechanism by which G4C2 repeats neurodegeneration unknown. Decreased tissue levels transcript implicate a loss protein function due to haploinsufficiency, intranuclear neuronal RNA foci have been observed in ALS FTD tissues, suggesting that may be toxic [1].
Abstract A pathological hallmark of neurodegenerative disease is the accumulation aberrant protein aggregates which contribute to cytotoxicity and are therefore a target for new therapy development. One key machinery manage cellular homeostasis chaperones proteins, heat shock proteins (HSPs) known including TDP-43, tau amyloid rescue neurodegeneration in various models. As an attempt HSP activation therapy, we develop drug screening assay search compounds that activate master regulator HSPs,...