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    Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1.
    Diseases 2016 Sep 8;4(3). Epub 2016 Sep 8.
    National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
    Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI) of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. Read More

    Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.
    Cancer Lett 2017 Sep 15. Epub 2017 Sep 15.
    Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:
    Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Read More

    The role of epigenetics in lysosomal storage disorders: Uncharted territory.
    Mol Genet Metab 2017 Aug 1. Epub 2017 Aug 1.
    Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, United States.
    The study of the contribution of epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, to human disease has enhanced our understanding of different cellular processes and diseased states, as well as the effect of environmental factors on phenotypic outcomes. Epigenetic studies may be particularly relevant in evaluating the clinical heterogeneity observed in monogenic disorders. The lysosomal storage disorders are Mendelian disorders characterized by a wide spectrum of associated phenotypes, ranging from neonatal presentations to symptoms that develop in late adulthood. Read More

    Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): findings from the International NPC Registry.
    World J Biol Psychiatry 2017 Sep 15:1-30. Epub 2017 Sep 15.
    h Mayo Clinic , Rochester MN , USA.
    Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognized by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry.

    Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Read More

    Exacerbating and reversing lysosomal storage diseases: from yeast to humans.
    Microb Cell 2017 Aug 25;4(9):278-293. Epub 2017 Aug 25.
    Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032.
    Lysosomal storage diseases (LSDs) arise from monogenic deficiencies in lysosomal proteins and pathways and are characterized by a tissue-wide accumulation of a vast variety of macromolecules, normally specific to each genetic lesion. Strategies for treatment of LSDs commonly depend on reduction of the offending metabolite(s) by substrate depletion or enzyme replacement. However, at least 44 of the ~50 LSDs are currently recalcitrant to intervention. Read More

    Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.
    Cell Rep 2017 Sep;20(11):2565-2574
    Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
    Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Read More

    A Carbon Nanotube Optical Reporter Maps Endolysosomal Lipid Flux.
    ACS Nano 2017 Sep 12. Epub 2017 Sep 12.
    Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
    Lipid accumulation within the lumen of endolysosomal vesicles is observed in various pathologies including atherosclerosis, liver disease, neurological disorders, lysosomal storage disorders, and cancer. Current methods cannot measure lipid flux specifically within the lysosomal lumen of live cells. We developed an optical reporter, composed of a photoluminescent carbon nanotube of a single chirality, that responds to lipid accumulation via modulation of the nanotube's optical band gap. Read More

    Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.
    Biochim Biophys Acta 2017 Sep 6. Epub 2017 Sep 6.
    Institute of Biochemistry, Graz University of Technology, Graz, Austria. Electronic address:
    Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Read More

    The Report of Three Rare Cases of the Niemann-pick Disease in Birjand, South Khorasan, Eastern Iran.
    Iran J Child Neurol 2017 ;11(3):53-56
    Pediatrics Endocrinology Department, Mashhad University of Medical Sciences, Mashhad, Iran.
    Niemann-Pick disease type C (NP-C) is a rare neurovisceral and irreversible disease leading to premature death and disabling neurological signs. This autosomal recessive disease with incidence rate of 1:120000 is caused by mutations in either the NPC1 or the NPC2 gene, which leads to accumulation of cholesterol in body tissues especially brain and progressive neurological symptoms. NP-C is characterized by nonspecific visceral, neurological and psychiatric manifestations in infants. Read More

    Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease.
    Mol Cell Proteomics 2017 Aug 31. Epub 2017 Aug 31.
    The Scripps Research Institute, United States;
    Niemann-Pick type C (NPC) disease is an inherited, progressive neurodegenerative disorder principally caused by mutations in the NPC1 gene. NPC disease is characterized by the accumulation of unesterified cholesterol in the late endosomes (LE) and lysosomes (LE) (LE/Ly). Vorinostat, a histone deacetylase inhibitor (HDACi), restores cholesterol homeostasis in fibroblasts derived from NPC patients; however, the exact mechanism by which Vorinostat restores cholesterol level is not known yet. Read More

    Activation of PKC triggers rescue of NPC1 patient specific iPSC derived glial cells from gliosis.
    Orphanet J Rare Dis 2017 Aug 25;12(1):145. Epub 2017 Aug 25.
    Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, 18147, Rostock, Germany.
    Background: Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. The pathological mechanisms, underlying NPC1 are not yet completely understood. Especially the contribution of glial cells and gliosis to the progression of NPC1, are controversially discussed. Read More

    Patient with Niemann-Pick disease type C: over 20 years' follow-up.
    BMJ Case Rep 2017 Aug 22;2017. Epub 2017 Aug 22.
    Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
    We report a 37-year-old woman with Niemann-Pick disease type C (NPC) 1. At the age of 8 years, she presented slow running followed by both fingers dystonia at the age of 10 years. At the age of 16 years, she developed declined scholastic achievement. Read More

    FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome.
    Pediatrics 2017 Jun;139(Suppl 3):S183-S193
    Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York.
    Background And Objective: Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Read More

    Prospective Turkish Cohort Study to Investigate the Frequency of Niemann-Pick Disease Type C Mutations in Consanguineous Families with at Least One Homozygous Family Member.
    Mol Diagn Ther 2017 Aug 14. Epub 2017 Aug 14.
    Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
    Background: Niemann-Pick disease Type C (NP-C) is a rare, autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. Diagnosis of NP-C can be challenging and is frequently delayed. Identifying mutations in individuals with NP-C and their relatives enables genetic counseling and prenatal diagnosis and may support earlier diagnosis. Read More

    Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.
    Lancet 2017 Aug 10. Epub 2017 Aug 10.
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD USA. Electronic address:
    Background: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. Read More

    Utility of rapid whole exome sequencing in the diagnosis of neonatal Niemann Pick disease type C presenting with fetal hydrops and liver failure.
    Cold Spring Harb Mol Case Stud 2017 Aug 11. Epub 2017 Aug 11.
    Boston Children's Hospital;
    Rapid whole exome sequencing (rWES) is increasingly used in critically ill newborn infants to inform about diagnosis, clinical management and prognosis. Here we report a male newborn infant with hydrops, pancytopenia and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure related morbidity and mortality and lack of diagnosis we employed rWES in the proband and both parents with a turn-around time of 10 business days. Read More

    Limited benefits of presymptomatic cord blood transplantation in neurovisceral acid sphingomyelinase deficiency (ASMD) intermediate type.
    Eur J Paediatr Neurol 2017 Jul 29. Epub 2017 Jul 29.
    Reference Centre for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France; UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address:
    Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. Read More

    3.3 Å structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.
    Proc Natl Acad Sci U S A 2017 Aug 7;114(34):9116-9121. Epub 2017 Aug 7.
    Laboratory of Cell Biology, The Rockefeller University, New York, NY 10065;
    Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Read More

    The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection.
    Antiviral Res 2017 Sep 3;145:96-102. Epub 2017 Aug 3.
    Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine, Kitasato University, Towada, Japan. Electronic address:
    Feline infectious peritonitis (FIP) is a feline coronavirus (FCoV)-induced fatal disease in wild and domestic cats. FCoV exists in two serotypes. Type I FCoV is the dominant serotype worldwide. Read More

    LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease.
    PLoS One 2017 27;12(7):e0181700. Epub 2017 Jul 27.
    Service de Biochimie et Biologie Moléculaire Grand Est, Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.
    Background: The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma.

    Methodology: We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i. Read More

    NMR analysis reveals significant differences in the plasma metabolic profiles of Niemann Pick C1 patients, heterozygous carriers, and healthy controls.
    Sci Rep 2017 Jul 24;7(1):6320. Epub 2017 Jul 24.
    Department of Pharmacology, De Montfort University, Leicester, UK.
    Niemann-Pick type C1 (NPC1) disease is a rare autosomal recessive, neurodegenerative lysosomal storage disorder, which presents with a range of clinical phenotypes and hence diagnosis remains a challenge. In view of these difficulties, the search for a novel, NPC1-specific biomarker (or set of biomarkers) is a topic of much interest. Here we employed high-resolution (1)H nuclear magnetic resonance spectroscopy coupled with advanced multivariate analysis techniques in order to explore and seek differences between blood plasma samples acquired from NPC1 (untreated and miglustat treated), heterozygote, and healthy control subjects. Read More

    Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience.
    J Pediatr 2017 Jul 17. Epub 2017 Jul 17.
    Newborn Screening Laboratory, Illinois Department of Public Health, Chicago, IL; Division of Laboratory Services, Tennessee Department of Health, Nashville, TN.
    Objectives: To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois.

    Study Design: Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago.

    Results: The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p. Read More

    The role of macrophages in interstitial lung diseases: Number 3 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.
    Eur Respir Rev 2017 Sep 19;26(145). Epub 2017 Jul 19.
    Unit of Pathologic Anatomy, Azienda ULSS 13, Hospital of Dolo, Dolo, Italy.
    The finding of collections of macrophages/histiocytes in lung biopsy and bronchoalveolar lavage is relatively common in routine practice. This morphological feature in itself is pathological, but the exact clinical significance and underlying disease should be evaluated together with clinical data, functional respiratory and laboratory tests and imaging studies.Morphological characteristics of macrophages and their distribution along the different pulmonary structures should be examined carefully by pathologists. Read More

    Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat.
    JIMD Rep 2017 Jul 15. Epub 2017 Jul 15.
    Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, VIC, Australia.
    Niemann-Pick disease type C (NPC) is a rare neurometabolic disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment currently available is miglustat, an iminosugar that inhibits the accumulation of lipid metabolites in neurons and other cells. This longitudinal diffusion tensor imaging (DTI) study examined how the rate of white matter change differed between treated and non-treated adult-onset NPC patient groups. Read More

    Modulating cancer cell survival by targeting intracellular cholesterol transport.
    Br J Cancer 2017 Aug 11;117(4):513-524. Epub 2017 Jul 11.
    Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
    Background: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. Read More

    Patient With Niemann-Pick Type C Presenting With a Jaw Mass Characterized With Lymph Node Involvement by Niemann-Pick Cells.
    J Pediatr Hematol Oncol 2017 Jul 7. Epub 2017 Jul 7.
    *Division of Pediatric Metabolism and Nutrition †Department of Pathology ‡Division of Pediatric Haematology and Oncology, Gazi University Hospital, Ankara, Turkey.
    Niemann-Pick type C disease (NPC) is an autosomal recessive disorder resulting in accumulation of unesterified lysosomal cholesterol. An 8-year-old girl with NPC disease had a painless, rigid, and fixed mass measuring 3 cm in diameter located on the left angular region of mandibula. The mass biopsy showed lipid-laden phagocytic cells infiltrating the lymph node consistent with Niemann-Pick cells. Read More

    Overview of immune abnormalities in lysosomal storage disorders.
    Immunol Lett 2017 Aug 4;188:79-85. Epub 2017 Jul 4.
    Centro Italiano Macula, Rome, Italy.
    The critical relevance of the lysosomal compartment for normal cellular function can be proved by numbering the clinical phenotypes that arise in lysosomal storage disorders (LSDs), a group of around 70 different monogenic autosomal or X-linked syndromes, caused by specific lysosomal enzyme deficiencies: all LSDs are characterized by progressive accumulation of heterogeneous biologic materials in the lysosomes of various parts of the body such as viscera, skeleton, skin, heart, and central nervous system. At least a fraction of LSDs has been associated with mixed abnormalities involving the immune system, while some patients with LSDs may result more prone to autoimmune phenomena. A large production of proinflammatory cytokines has been observed in Gaucher and Fabry diseases, and wide different autoantibody production has been also reported in both. Read More

    Expanded carrier screening for monogenic disorders: where are we now?
    Prenat Diagn 2017 Jul 6. Epub 2017 Jul 6.
    Centre for Biomedical Ethics and Law, Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium.
    Background: Expanded carrier screening (ECS), which can identify carriers of a large number of recessive disorders in the general population, has grown in popularity and is now widely accessible to prospective parents. This article presents a comprehensive overview of the characteristics of currently available ECS tests.

    Methods: To identify relevant ECS providers, we employed a multi-step approach, which included online searching, review of the recent literature, and consultations with researchers familiar with the current landscape of ECS. Read More

    Early Hippocampal i-LTP and LOX-1 Overexpression Induced by Anoxia: A Potential Role in Neurodegeneration in NPC Mouse Model.
    Int J Mol Sci 2017 Jul 5;18(7). Epub 2017 Jul 5.
    Department of Medical System, University of Rome Tor Vergata, Rome 00133, Italy.
    Niemann-Pick type C disease (NPCD) is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endo-lysosomal compartment of cells. In the central nervous system, hypoxic insults could result in low-density lipoprotein (LDL) oxidation and Lectin-like oxidized LDL receptor-1 (LOX-1) induction, leading to a pathological hippocampal response, namely, ischemic long-term potentiation (i-LTP). These events may correlate with the progressive neural loss observed in NPCD. Read More

    Decreased calcium flux in Niemann-Pick type C1 patient-specific iPSC-derived neurons due to higher amount of calcium-impermeable AMPA receptors.
    Mol Cell Neurosci 2017 Sep 27;83:27-36. Epub 2017 Jun 27.
    Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, D-18147 Rostock, Germany. Electronic address:
    Niemann-Pick disease type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene, resulting mainly in the accumulation of cholesterol and the ganglioside GM2. Recently, we described accumulations of these lipids in neuronal differentiated cells derived from NPC1 patient-specific induced pluripotent stem cells (iPSCs). As these lipids are essential for proper cell membrane composition, we were interested in the expression and function of voltage-gated ion channels and excitatory AMPA receptors (AMPARs) in neurons derived from three patient-specific iPSC lines. Read More

    ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement.
    J Drug Target 2017 Jul 14:1-10. Epub 2017 Jul 14.
    b Institute for Bioscience & Biotechnology Research , University of Maryland , College Park , MD , USA.
    Enzyme replacement is a viable treatment for diseases caused by genetic deficiency of lysosomal enzymes. However, suboptimal access of enzymes to target sites limits this strategy. Polymer nanocarriers (NCs) coated with antibody against intercellular adhesion molecule 1 (ICAM-1), a protein overexpressed on most cells under disease states, enhanced biodistribution and lysosomal delivery of these therapeutics. Read More

    Cognition and anatomy of adult Niemann-Pick disease type C: Insights for the Alzheimer field.
    Cogn Neuropsychol 2017 Jun 30:1-14. Epub 2017 Jun 30.
    a Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques , CHU de Québec , Quebec City , Quebec , Canada.
    Niemann-Pick disease type C (NPC) is a rare lysosomal storage disorder causing an intracellular lipid trafficking defect and varying damage to the spleen, liver, and central nervous system. The adult form, representing approximately 20% of the cases, is associated with progressive cognitive decline. Intriguingly, brains of adult NPC patients exhibit neurofibrillary tangles, a characteristic hallmark of Alzheimer's disease (AD). Read More

    The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes.
    Cell Rep 2017 Jun;19(13):2823-2835
    Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China. Electronic address:
    Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown. Read More

    Analytical Characterization of Methyl-β-Cyclodextrin for Pharmacological Activity to Reduce Lysosomal Cholesterol Accumulation in Niemann-Pick Disease Type C1 Cells.
    Assay Drug Dev Technol 2017 May/Jun;15(4):154-166
    1 National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda, Maryland.
    Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Read More

    Impact of the Niemann-Pick c1 Gene Mutation on the Total Cellular Glycomics of CHO Cells.
    J Proteome Res 2017 Aug 3;16(8):2802-2810. Epub 2017 Jul 3.
    Graduate School of Advanced Life Science, Hokkaido University , Sapporo 001-0021, Japan.
    Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, and the majority of cases are caused by mutations in the NPC1 gene. In this study, we clarified how a single gene mutation in the NPC1 gene impacts the cellular glycome by analyzing the total glycomic expression profile of Chinese hamster ovary cell mutants defective in the Npc1 gene (Npc1 KO CHO cells). A number of glycomic alterations were identified, including increased expression of lactosylceramide, GM1, GM2, GD1, various neolacto-series glycosphingolipids, and sialyl-T (O-glycan), which was found to be the major sialylated protein-bound glycan, as well as various N-glycans, which were commonly both fucosylated and sialylated. Read More

    Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments.
    FEBS J 2017 Aug 6;284(15):2513-2526. Epub 2017 Jul 6.
    Izmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, Izmir, Turkey.
    While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Read More

    Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK.
    Autophagy 2017 Aug 14;13(8):1435-1451. Epub 2017 Jun 14.
    a National Center for Advancing Translational Sciences (NCATS), NIH , Bethesda , MD , USA.
    The drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease, type C (NPC) and has been advanced to human clinical trials. However, its mechanism of action for reducing cholesterol accumulation in NPC cells is uncertain and its molecular target is unknown. We found that methyl-β-cyclodextrin (MβCD), a potent analog of HPβCD, restored impaired macroautophagy/autophagy flux in Niemann-Pick disease, type C1 (NPC1) cells. Read More

    N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV.
    Neurobiol Dis 2017 Sep 10;105:257-270. Epub 2017 Jun 10.
    Dominick P. Purpura Dept. of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:
    Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Read More

    Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice.
    Mol Ther 2017 Jul 9;25(7):1686-1696. Epub 2017 Jun 9.
    Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, MD 20742, USA; Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA. Electronic address:
    Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Read More

    Imipramine Inhibits Chikungunya Virus Replication in Human Skin Fibroblasts through Interference with Intracellular Cholesterol Trafficking.
    Sci Rep 2017 Jun 9;7(1):3145. Epub 2017 Jun 9.
    Laboratoire MIVEGEC, UMR 224 IRD/CNRS/UM1, Montpellier cedex 5, 34394, France.
    Chikungunya virus (CHIKV) is an emerging arbovirus of the Togaviridae family that poses a present worldwide threat to human in the absence of any licensed vaccine or antiviral treatment to control viral infection. Here, we show that compounds interfering with intracellular cholesterol transport have the capacity to inhibit CHIKV replication in human skin fibroblasts, a major viral entry site in the human host. Pretreatment of these cells with the class II cationic amphiphilic compound U18666A, or treatment with the FDA-approved antidepressant drug imipramine resulted in a near total inhibition of viral replication and production at the highest concentration used without any cytotoxic effects. Read More

    Induced pluripotent stem cell models of lysosomal storage disorders.
    Dis Model Mech 2017 Jun;10(6):691-704
    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models. Read More

    Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole.
    Elife 2017 Jun 7;6. Epub 2017 Jun 7.
    Department of Molecular Cell Biology and Anatomy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
    Niemann-Pick type C is a storage disease caused by dysfunction of NPC proteins, which transport cholesterol from the lumen of lysosomes to the limiting membrane of that compartment. Using freeze fracture electron microscopy, we show here that the yeast NPC orthologs, Ncr1p and Npc2p, are essential for formation and expansion of raft-like domains in the vacuolar (lysosome) membrane, both in stationary phase and in acute nitrogen starvation. Moreover, the expanded raft-like domains engulf lipid droplets by a microautophagic mechanism. Read More

    Miglustat therapy in a case of early-infantile Niemann-Pick type C.
    Brain Dev 2017 Jun 3. Epub 2017 Jun 3.
    Department of Pediatrics, Jichi Medical University, Tochigi, Japan. Electronic address:
    Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPC1 or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Read More

    Ocular findings in patients with cholestatic disorders of infancy: A single-centre experience.
    Arab J Gastroenterol 2017 Jun 3;18(2):108-113. Epub 2017 Jun 3.
    Faculty of Pharmacy, Misr International University, Cairo, Egypt.
    Background And Study Aims: Neonatal cholestasis can be associated with ocular findings that might aid in its diagnosis, e.g., Alagille syndrome (AGS) and Niemann Pick disease (NPD). Read More

    Niemann-Pick type C as a cause of progressive intellectual and neurological deterioration in childhood.
    Dev Med Child Neurol 2017 Sep 2;59(9):965-972. Epub 2017 Jun 2.
    PIND Research Group, Addenbrooke's Hospital, Cambridge, UK.
    Aim: To describe the cases of Niemann-Pick type C (NP-C) disease in a United Kingdom epidemiological study of progressive intellectual and neurological deterioration in childhood.

    Method: Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015.

    Results: Fifty-three NP-C patients were identified: 29 females, 24 males. Read More

    Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick type C1 disease in a 7-week-old male with cholestasis.
    Cold Spring Harb Mol Case Stud 2017 Sep 1;3(5). Epub 2017 Sep 1.
    Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.
    Niemann-Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1 Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS). Read More

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