A5013600781- Amyotrophic Lateral Sclerosis Research
- Mitochondrial Function and Pathology
- Alzheimer's disease research and treatments
- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- Pluripotent Stem Cells Research
- Parkinson's Disease Mechanisms and Treatments
- Neurological diseases and metabolism
- Hereditary Neurological Disorders
- Prion Diseases and Protein Misfolding
- Metabolism and Genetic Disorders
- Biomedical Ethics and Regulation
- RNA Research and Splicing
- RNA regulation and disease
- Neurogenesis and neuroplasticity mechanisms
- Coenzyme Q10 studies and effects
- Adenosine and Purinergic Signaling
- Genetics and Neurodevelopmental Disorders
- Autophagy in Disease and Therapy
- Neuroscience and Neuropharmacology Research
- ATP Synthase and ATPases Research
- Ion channel regulation and function
- Porphyrin Metabolism and Disorders
- Neurological disorders and treatments
- Botulinum Toxin and Related Neurological Disorders
University College London
2012-2022
National Hospital for Neurology and Neurosurgery
2012-2022
King's College London
2012
In this study, we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance craniocervical dystonia. Subsequent screening these large number familial and sporadic cases cervical dystonia led the identification total six putatively pathogenic mutations ANO3, gene encoding predicted Ca2+-gated chloride channel that show be highly expressed striatum. Functional studies...
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, a common extended haplotype spanning across MAPT locus is associated with increased risk of PSP Parkinson's disease.We identified rare variant (p.A152T) patient clinical diagnosis assessed its frequency multiple independent series patients neurodegenerative conditions...
Report7 November 2017Open Access Transparent process G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and vivo Roberto Simone Department of Neurodegenerative Disease, UCL Institute Neurology, London, UK Search for more papers by this author Rubika Balendra Genetics, Evolution Environment, Healthy Ageing, University College Thomas G Moens Elisavet Preza Molecular Neuroscience, Katherine M Wilson Amanda Heslegrave Nathan S Woodling Teresa Niccoli Javier...
The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that clinically classified as either pure with predominant lower limb spasticity, or complex where paraplegia is complicated additional neurological features, and inherited in autosomal dominant, recessive X-linked patterns. Genetic defects have been identified over 40 different genes, more than 70 loci total. Complex the past frequently associated mutations SPG11 (spatacsin), ZFYVE26/SPG15, SPG7...
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction sequence molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations spinal cord MNs ACs. We identify significantly increased cytoplasmic TDP-43 ER stress as primary pathogenic patient-specific valosin-containing protein...
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are cause inclusion body myopathy, Paget's disease bone, and frontotemporal dementia (IBMPFD) they account for 1%-2% familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic in gene, we show that deficiency causes profound mitochondrial uncoupling leading to decreased membrane potential increased oxygen consumption. This...
Our understanding of the molecular mechanisms many neurological disorders has been greatly enhanced by discovery mutations in genes linked to familial forms these diseases. These have facilitated generation cell and animal models that can be used understand underlying pathology. Recently, there a surge interest use patient-derived cells, due development induced pluripotent stem cells their subsequent differentiation into neurons glia. Access patient lines carrying relevant is limiting factor...
The alternative splicing of the tau gene, MAPT, generates six protein isoforms in adult human central nervous system (CNS).Tau is developmentally regulated and dysregulated disease.Mutations MAPT that alter cause frontotemporal dementia (FTD) with pathology, providing evidence for a causal link between altered disease.The use induced pluripotent stem cell (iPSC)-derived neurons has revolutionized way we model neurological disease vitro.However, as most mutations are located within or around...
Abstract Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which disease not properly understood but a favoured route involves its translation into dipeptide (DPR) polypeptides, some neurotoxic. However, precise targets for mutant DPR toxicity fully clear, damage to several neuronal functions has been described. Many these regulated signalling between endoplasmic reticulum...
An expanded hexanucleotide repeat in the C9orf72 gene is most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0–30 repeats are present general population, expansions >500 associated with C9ALS/FTD. Large C9ALS/FTD share a haplotype whether these derive from single founder or occur more frequently on predisposing yet to be determined relevant disease pathomechanisms. Furthermore, although cases carrying 50–200 have been described, their...
<h3>Background</h3> The autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. large number ARCA genes leads to delay difficulties obtaining an exact diagnosis in many patients families. Ubiquinone (CoQ10) deficiency is one the potentially treatable causes ARCAs as some respond CoQ10 supplementation. AarF domain containing kinase 3 gene (<i>ADCK3</i>) several associated with deficiency. <i>ADCK3</i> encodes...
Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. has a role the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but neuropathological mechanism and reasons for accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) subsequently differentiated cortical neuronal studying disease mechanisms human neurons. We observed no changes expression between control patient cells,...
<h3>Objective</h3> Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although number genes have been identified for CMT, the gene discovery some complex form CMT has lagged behind. The association neuropathy optic atrophy (also known as type 6) described with autosomaldominant, recessive X-linked modes inheritance. Mutations in Mitofusin 2 found to cause dominant CMT6. Phosphoribosylpyrophosphate synthetase-I mutations CMT6, but until now,...
Mutations in microtubule-associated protein tau (MAPT) gene are causative of Frontotemporal Dementia (FTD). Many the features associated with development pathology, e.g high levels phosphorylation, also present early development. iPSC-neurons have expression signatures similar to fetal neurons, and MAPT mutations do not develop aggregates. We hypothesise that resistant developing aggregates due activity proteostasis network during To test this hypothesis, we investigated proteasome subunits...
A non-coding hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. In order to generate physiologically-relevant cell models mediated FTD study disease mechanisms, we have generated iPSC from 3 patient fibroblast lines carrying mutation. were by retroviral expression pluripotency-associated transcription factors Oct3/4, Sox2, Klf4 cMyc. Fibroblasts expressing reprogramming maintained on SNL feeder cells for 25–30 days...