A5079479806- Neurobiology and Insect Physiology Research
- RNA regulation and disease
- Circadian rhythm and melatonin
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Insect and Arachnid Ecology and Behavior
- Ion channel regulation and function
- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- RNA and protein synthesis mechanisms
- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Plant Molecular Biology Research
- Genetics and Neurodevelopmental Disorders
- Neurological diseases and metabolism
- Hereditary Neurological Disorders
- Neuroscience and Neural Engineering
- Endoplasmic Reticulum Stress and Disease
- RNA modifications and cancer
- Pancreatic function and diabetes
- Autophagy in Disease and Therapy
- Neuroscience and Neuropharmacology Research
- Photoreceptor and optogenetics research
- Plant and Biological Electrophysiology Studies
- Insect and Pesticide Research
University College London
2014-2024
National Hospital for Neurology and Neurosurgery
2017-2024
Thomas Jefferson University
2012-2020
Jefferson Hospital for Neuroscience
2014-2020
Sidney Kimmel Cancer Center
2012-2015
Brown University
2007-2013
University of Oxford
2005-2006
Oxford Brookes University
2005
John Radcliffe Hospital
2005
Abstract AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients intellectual disability (ID) neurodevelopmental...
Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 SLC52A3, have recently been linked syndrome. However, the genetic frequency, neuropathology downstream consequences are unclear. By screening large cohort 132 patients early-onset severe motor neuropathy we confirmed...
Sleep is a highly conserved and essential behaviour in many species, including the fruit fly Drosophila melanogaster. In wild, sensory signalling encoding environmental information must be integrated with sleep drive to ensure that not initiated during detrimental conditions. However, molecular circuit mechanisms by which timing modulated environment are unclear. Here we introduce novel behavioural paradigm study this issue. We show male flies, onset of daytime siesta delayed ambient...
Objective To identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods We performed genome‐wide sequencing, homozygosity mapping, segregation analysis for novel gene discovery. used circular dichroism to show secondary structure changes isothermal titration calorimetry investigate the impact of on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays mass...
Select proteins involved in electrical and chemical neurotransmission are re-coded at the RNA level via deamination of particular adenosines to inosine by adenosine deaminases acting on (ADARs). It has been hypothesized that this process, termed editing, acts "fine-tune" neurophysiological properties animals potentially downstream behavioral outputs. However, extreme phenotypes resulting from deletions adar loci have precluded investigations into relationship between ADAR levels, target...
Rasmussen encephalitis (RE) sera were screened for antibodies to human α7 nicotinic acetylcholine receptors (nAChRs) using electrophysiology, calcium imaging, and ligand binding assays. Sera from two of nine patients with RE blocked ACh-induced currents through nAChRs the rise in intracellular free ([Ca<sup>2+</sup>]<sub>i</sub>) inhibited <sup>125</sup>I-α-bungarotoxin cells expressing nAChRs. Thus, nAChR is a potential target pathogenic RE.
Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns has been extensively characterized. contrast, genetic loci involved in linking to alterations motor activity have remained elusive. a forward-genetic screen, we uncovered new component output pathway, which termed dyschronic (dysc). dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms normal protein cycling remains intact....
Mutations in the Golgi SNARE (SNAP [soluble NSF attachment protein] receptor) protein Membrin (encoded by GOSR2 gene) cause progressive myoclonus epilepsy (PME). is a ubiquitous and essential mediating ER-to-Golgi membrane fusion. Thus, it unclear how mutations result disorder restricted to nervous system. Here, we use multi-layered strategy elucidate consequences of from neuron. We show that pathogenic partial reductions SNARE-mediated Importantly, these alterations were sufficient...
Synaptic scaffold proteins control the localization of ion channels and receptors, facilitate molecular associations between signaling components that modulate synaptic transmission plasticity. Here, we define novel roles for a recently described protein, Dsychronic (DYSC), at Drosophila larval neuromuscular junction. DYSC is homolog whirlin/DFNB31, PDZ domain protein linked to Usher syndrome, most common form human deaf-blindness. We show expressed presynaptically often localized adjacent...
Abstract Experimental biological model system outcomes such as altered animal movement capability or behaviour are difficult to quantify manually. Existing automatic tracking devices can be expensive and imposing upon the typical environment of model. We have developed a novel multiplatform, free-to-use open-source application based on OpenCV, called AnimApp. Our results show that AnimApp reliably reproducibly track small animals rodents insects, parameters action including distance speed in...
Abstract Background Paroxysmal dyskinesias (PxDs) are characterized by involuntary movements and altered pre‐motor circuit activity. Causative mutations provide a means to understand the molecular basis of PxDs. Yet in many cases, animal models harboring corresponding lacking. Here we utilize fruit fly, Drosophila , study PxD linked gain‐of‐function (GOF) mutation KCNMA1 /hSlo1 BK potassium channel. Objectives We aimed recreate equivalent (big potassium) channel . sought determine how this...
Regulated point modification by an RNA editing enzyme occurs at four conserved sites in the Drosophila Shaker potassium channel. Single mRNA molecules can potentially represent any of 24 = 16 permutations (isoforms) these natural variants. We generated isoform expression profiles to assess sexually dimorphic, spatial, and temporal differences. Striking tissue-specific was seen for particular isoforms. Moreover, distributions showed evidence coupling (linkage) sites. Genetic manipulations...
Sleep-like states in diverse organisms can be separated into distinct stages, each with a characteristic arousal threshold. However, the molecular pathways underlying different sleep stages remain unclear. The fruit fly, Drosophila melanogaster, exhibits consolidated during both day and night, night associated higher thresholds compared to sleep. Here we identify role for neuronal calcium sensor protein Neurocalcin (NCA) promoting but not by suppressing nocturnal hyperactivity. We show that...
Adenosine deaminases acting on RNA (ADARs) catalyze the deamination of adenosine to inosine in double-stranded templates, a process known as editing. In Drosophila, multiple ADAR isoforms are generated from single locus (dAdar) via post-transcriptional modifications. Collectively, these act edit wide range transcripts involved neuronal signaling, well precursors endogenous small interfering RNAs. The phenotypic consequences loss dADAR activity have been characterized and consist profound...
Abstract Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy an essential housekeeping mechanism, which causes severe proteotoxic stress when impaired. impairment has been associated epileptogenesis through variety of molecular mechanisms. Vici Syndrome (VS) the paradigmatic congenital autophagy disorder in humans recessive variants ectopic P-granules tethering factor 5 ( EPG5 ) gene crucial...