A5027544640- Lysosomal Storage Disorders Research
- Calcium signaling and nucleotide metabolism
- Cellular transport and secretion
- Sphingolipid Metabolism and Signaling
- Retinal Development and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Lipid Membrane Structure and Behavior
- Insect Resistance and Genetics
- Carbohydrate Chemistry and Synthesis
- Pineapple and bromelain studies
- Alzheimer's disease research and treatments
- Endoplasmic Reticulum Stress and Disease
- Adenosine and Purinergic Signaling
- Cytomegalovirus and herpesvirus research
- Ion Channels and Receptors
- Tryptophan and brain disorders
- Piperaceae Chemical and Biological Studies
- Cholesterol and Lipid Metabolism
- Transgenic Plants and Applications
- Autoimmune and Inflammatory Disorders Research
- Data-Driven Disease Surveillance
- Proteins in Food Systems
- Glycosylation and Glycoproteins Research
- Acute Lymphoblastic Leukemia research
- COVID-19 epidemiological studies
Cardiff University
2016-2025
University of Oxford
2003-2017
University of Michigan
2016-2017
The Francis Crick Institute
2017
Mansfield University
2009
Weizmann Institute of Science
2003-2004
National Institutes of Health
2003
Presenilin 1 (PS1) deletion or Alzheimer's disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation instability of vATPase V0a1 subunit, causing deficient assembly function. We further demonstrate elevated pH in knockout (PS1KO) cells induces abnormal Ca(2+) efflux lysosomes mediated by TRPML1 elevates cytosolic Ca(2+). In WT cells, blocking activity knockdown either PS1...
SummaryIntracellular Ca2+ signals constitute key elements in signal transduction. Of the three major mobilizing messengers described, most potent, nicotinic acid adenine dinucleotide phosphate (NAADP) is least well understood terms of its molecular targets [1]. Recently, we showed that heterologous expression two-pore channel (TPC) proteins enhances NAADP-induced release, whereas NAADP response was abolished pancreatic beta cells from Tpcn2 gene knockout mice [2]. However, whether TPCs...
Glycosphingolipids are endocytosed and targeted to the Golgi apparatus but mistargeted lysosomes in sphingolipid storage disorders. Substrate reduction therapy utilizes imino sugars inhibit glucosylceramide synthase potentially abrogate effects of storage. Niemann-Pick type C (NPC) disease is a disorder intracellular transport where glycosphingolipids (GSLs) cholesterol accumulate endosomal compartments. The mechanisms altered trafficking not known may involve mistargeting disrupted function...
ABSTRACT Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event Alzheimer's disease (AD) pathogenesis. However, mechanisms underlying these abnormalities unclear. The transient receptor potential channel mucolipin 1(TRPML1, also known as MCOLN1), a vital endosomal-lysosomal Ca2+ whose loss of function leads to neurodegeneration, has not been investigated with respect EAL pathogenesis late-onset AD (LOAD). Here, we identify pathological hallmarks TRPML1...
We recently demonstrated that elevation of intracellular glucosylceramide (GlcCer) levels results in increased functional Ca2+ stores cultured neurons, and suggested this may be due to modulation ryanodine receptors (RyaRs) by GlcCer (Korkotian, E., Schwarz, A., Pelled, D., Schwarzmann, G., Segal, M. Futerman, A. H. (1999) J. Biol. Chem. 274, 21673–21678). now systematically examine the effects exogenously added GlcCer, other glycosphingolipids (GSLs) their lyso-derivatives on release from...
Gangliosides are found at high levels in neuronal tissues where they play a variety of important functions. In the gangliosidoses, gangliosides accumulate because defective activity lysosomal proteins responsible for their degradation, usually resulting rapidly progressive neurodegenerative disease. However, molecular mechanism(s) leading from ganglioside accumulation to neurodegeneration is not known. We now examine effect GM2 mouse model Sandhoff disease (one gangliosidoses), Hexb–/–...
Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources the uptake of low-density lipoproteins. complex, multienzyme-catalyzed pathway involving series sequentially acting enzymes. Inherited defects genes encoding cholesterol biosynthetic enzymes other regulators homeostasis result severe metabolic diseases, which are rare general population currently without effective therapy. Historically, these...
Abnormal accumulation of undigested macromolecules, often disease-specific, is a major feature lysosomal and neurodegenerative disease frequently attributed to defective autophagy. The mechanistic underpinnings the autophagy defects are subject intense research, which aided by genetic models. To gain an improved understanding pathways regulating specifically in juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), childhood, we developed piloted GFP-microtubule-associated protein...
The neuronal ceroid lipofuscinoses (NCLs) are the most common cause of childhood dementia and invariably fatal. Early localized glial activation occurs in these disorders, accurately predicts where loss is pronounced. Recent evidence suggests that dysfunction may contribute to neuron loss, we have now explored this possibility infantile NCL (INCL, CLN1 disease). We grew primary cultures astrocytes, microglia, neurons derived from Ppt1 deficient mice (Ppt1−/−) assessed their properties...
A nuclear localisation sequence (NLS) peptide, PAAKRVKLD, derived from the human c-Myc regulator gene, has been functionalised with a long wavelength (λ ex = 550 nm; λ em 677 nm) cyclometalated organometallic iridium(iii) complex to give conjugate Ir-CMYC. Confocal fluorescence microscopy studies on fibroblast cells imaged after 18-24 h incubation show that Ir-CMYC concentrations of 80-100 μM promote good cell uptake and localisation, which was confirmed though co-localisation using Hoechst...
Background The ongoing pandemic has placed an unprecedented strain on global society, health care, governments, and mass media. Public dissemination of government policies, medical interventions, misinformation been remarkably rapid largely unregulated during the COVID-19 pandemic, resulting in increased misinterpretations, miscommunication, public panic. Being first full-scale digital age, presented novel challenges pertinent to advice, spread news misinformation, trade-off between...
Variants identified in genome-wide association studies have implicated immune pathways the development of Alzheimer's disease (AD).Here, we investigated mechanistic basis for protection from AD associated with PLCc2 R522, a rare coding variant PLCG2 gene.We studied variant's role macrophages and microglia newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) knockin mice, which exhibit normal endogenous expression.In all models, cells expressing R522 mutation...