DOCSLIB.ORG

Glucocerebrosidase 2 Gene Deletion Rescues Type 1 Gaucher Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Glucocerebrosidase 2 Gene Deletion Rescues Type 1 Gaucher Disease Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease Pramod K. Mistrya,1, Jun Liua,2, Li Sunb,c,2, Wei-Lien Chuangd, Tony Yuenb,c,e, Ruhua Yanga, Ping Lub,c, Kate Zhangd, Jianhua Lib,c, Joan Keutzerd, Agnes Stachnikb,c, Albert Mennonea, James L. Boyera, Dhanpat Jaina, Roscoe O. Bradyf, Maria I. Newb,e,1, and Mone Zaidib,c,1 aDepartment of Medicine, Yale School of Medicine, New Haven, CT 06520; bMount Sinai Bone Program, cDepartment of Medicine, and eDepartment of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029; dGenzyme Sanofi, Framingham, MA 01701; and fNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20824 Contributed by Maria I. New, February 19, 2014 (sent for review December 11, 2013) The inherited deficiency of the lysosomal glucocerebrosidase basis of phenotypic diversity, unravel disease mechanism, and (GBA) due to mutations in the GBA gene results in Gaucher disease develop therapies have prompted the generation of mouse (GD). A vast majority of patients present with nonneuronopathic, models that recapitulate human GD1 (7–9). To this end, we have + type 1 GD (GD1). GBA deficiency causes the accumulation of two developed a GD1 mouse, Mx1–Cre :GD1, in which the Gba gene key sphingolipids, glucosylceramide (GL-1) and glucosylsphingo- is deleted in hematopoietic and mesenchymal lineage cells (4, 10, sine (LysoGL-1), classically noted within the lysosomes of mono- 11). This mouse displays hepatosplenomegaly, cytopenia, osteope- nuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced nia, Th1/Th2 hypercytokinemia, and an array of defects in early T- by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 cell maturation, B-cell recruitment, and antigen presentation (4, 10). pathophysiology is not known. We recently recapitulated hepatos- Glucosylceramide synthase in Golgi complex converts ceramide plenomegaly, cytopenia, hypercytokinemia, and the bone-forma- to GL-1, which is used in the production of more complex tion defect of human GD1 through conditional deletion of Gba glycosphingolipids. As membranes turn over in the lysosome, + in Mx1–Cre :GD1 mice. Here we show that the deletion of Gba2 lysosomal glycosidases sequentially cleave off the sugar residues significantly rescues the GD1 clinical phenotype, despite enhanced from nonreducing end of glycosphingolipids, and GL-1 is even- elevations in GL-1 and LysoGL-1. Most notably, the reduced bone tually hydrolyzed to ceramide and glucose by lysosomal GBA. In volume and bone formation rate are normalized. These results sug- addition, acid ceramidase exhibits expanded enzymatic activity to gest that metabolism of GL-1 or LysoGL-1 into downstream bioac- deacylate GL-1 to LysoGL-1, which is then converted to sphin- tive lipids is a major contributor to the bone-formation defect. Direct gosine by GBA2 (Fig. 1A) (12–14). GBA deficiency in GD1 thus testing revealed a strong inhibition of osteoblast viability by nano- results in the accumulation of GL-1 and LysoGL-1 in lysosomes molar concentrations of sphingosine, but not of ceramide. These and subsequently in the cytosol (Fig. 1B) (15). Hence, cytosolic findings are consistent with toxicity of high circulating sphingosine GL-1 and LysoGL-1 potentially become substrates for the extra- levels in GD1 patients, which decline upon enzyme-replacement lysosomal neutral GBA, encoded by GBA2, which should result in therapy; serum ceramide levels remain unchanged. Together, com- the production of ceramide and sphingosine, respectively (16, 17). plementary results from mice and humans affected with GD1 not We speculate that if ceramide and/or sphingosine are the ac- only pinpoint sphingosine as being an osteoblast toxin, but also set tive disease-causing agents in GD1, then deleting Gba2 in Mx1– + forth Gba2 as a viable therapeutic target for the development of Cre :GD1 mice will rescue aspects of the GD1 phenotype, de- inhibitors to ameliorate certain disabling consequences of GD1. spite enhanced elevations of GL-1 and LysoGL-1 (Fig. 1C). We report visceral, hematologic, skeletal, and partial cytokine rescue macrophage | knockout mice | S1P of the GD1 phenotype in compound mutant mice. We also show aucher disease (GD) is the most common lysosomal storage Significance Gdisorder, with a frequency as high as 1 in 850 live births in Ashkenazi Jews. Inherited deficiency of lysosomal glucocere- Type 1 Gaucher disease (GD1) is a rare autosomal recessive brosidase (GBA) arising from biallelic mutations in the GBA – disorder caused by inherited mutations in the glucocerebrosidase gene underlies the clinical phenotype of GD (1 3). As a conse- (GBA1) gene. This disease results in a marked accumulation quence, the glucosphingolipids glucosylceramide (GL-1) and glu- of glycosphingolipid substrates, causing visceromegaly, cyto- cosylsphingosine (LysoGL-1) accumulate conspicuously within the penia, and osteopenia. Here, we have rescued this clinical – lysosomes of mononuclear phagocytes (1 4). These lipids spill phenotype in GD1 mice by genetically deleting Gba2, a gene over into circulation with modest elevation in serum GL-1 levels, encoding a downstream extralysosomal enzyme, GBA2. We but with dramatic increases in LysoGL-1 due to its high solubility also report that sphingosine production in GD1 patients may (5). It is not understood, however, how the metabolites of GL-1 contribute to the low-turnover bone loss. Our data suggest and LysoGL-1 produced by extralysosomal glucocerebrosidase that GBA2 and sphingosine are potential targets for pharma- (GBA2) contribute to GD pathophysiology. cological intervention in GD1 patients. Nonneuronopathic type 1 GD (GD1) manifests classically with striking hepatosplenomegaly, profound cytopenia, and a complex Author contributions: P.K.M., J.K., J.L.B., R.O.B., M.I.N., and M.Z. designed research; J. Liu, pattern of severe skeletal disease. However, some GD1 patients L.S., W.-L.C., R.Y., P.L., J. Li, A.S., and A.M. performed research; K.Z. contributed new reagents/analytic tools; P.K.M., J. Liu, L.S., W.-L.C., T.Y., K.Z., A.S., J.L.B., D.J., R.O.B., and can display broader phenotypes, including neurodegeneration, M.Z. analyzed data; and P.K.M., T.Y., M.I.N., and M.Z. wrote the paper. autoimmune diathesis, lymphoproliferative neoplasms, and Conflict of interest statement: P.K.M. and M.Z. have received honoraria and/or consulting osteopenia (1, 3). Furthermore, there is unexplained phenotypic fees from Genzyme. GBA variability among patients harboring identical mutations, 1To whom correspondence may be addressed. E-mail: [email protected], maria. between affected sibling pairs, and even between identical twins [email protected], or [email protected]. (6). Enzyme-replacement therapy (ERT) with macrophage-tar- 2J. Liu and L.S. contributed equally to this work. geted, recombinant glucocerebrosidase ameliorates certain, but This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. not all of, the manifestations (1). Thus, efforts to understand the 1073/pnas.1400768111/-/DCSupplemental. 4934–4939 | PNAS | April 1, 2014 | vol. 111 | no. 13 www.pnas.org/cgi/doi/10.1073/pnas.1400768111 Downloaded by guest on September 25, 2021 Fig. 1. Aberration of sphingolipid pathways in Gba deficiency. (A) In normal mice, the lipid substrate glucosylceramide (GL-1) is converted by the lysosomal acid glucocerebrosidase Gba to ceramide and by ceramidase to glucosylsphingosine (LysoGL-1). (B) In Gba deficiency, the accumulating GL-1 and LysoGL-1 spill over into the cytoplasm, where the extralysosomal neutral glucocerebrosidase Gba2 converts them to ceramide and sphingosine, respectively. (C) We predict that if the defects in GD are due to products of GL-1 and LysoGL-1—namely, sphingosine or ceramide—the Gba−/− phenotype will be rescued in vivo by the deletion of Gba2. that sphingosine, but not ceramide, inhibits osteoblast survival extralysosomal Gba2 as a target to control at least some aspects of and that GD1 patients display elevated sphingosine levels that B-cell involvement in GD1. Group B cytokines, including IL-3, -13, are reduced upon imiglucerase therapy. The data identify monocyte chemotatic protein-1 (MCP-1), and TNF-α, were in- + sphingosine as one molecular mediator of GD1 pathophysiology creased in Mx1–Cre :GD1 mice, but were not sensitive to Gba2 and suggest that the extralysosomal GBA2 could potentially be deletion either alone or in combination with Gba deletion. targeted to ameliorate certain disabling manifestations of GD1. Group C cytokines that included IL-2, -6, granulocyte colony- stimulating factor (G-CSF), and keratinocyte-derived chemokine + Results (KC) were all elevated in Mx1–Cre :GD1 mice, but suppressed −/− We hypothesized that Gba2-encoded extralysosomal glucocere- in global Gba2 mice, compared with controls. Reduction of brosidase plays a pivotal role in GD pathophysiology. Having these Th1 cytokines in GD1 by targeting Gba2 may provide + generated a Mx1–Cre :GD1 mouse that recapitulates human additional therapeutic benefit in attenuating the accompanying GD1, we sought to delete Gba2 in this mouse to generate a systemic inflammation. Group D cytokines comprised IL-1β, + −/− compound Mx1–Cre :GD1:Gba2 mouse with a goal to rescue -9, macrophage inflammatory protein-1-beta (MIP-1β), and IFN- the GD1 clinical phenotype. To generate this mouse, we crossed γ, which were elevated in response to both Gba and Gba2 de- fl/fl fl/− Gba floxed mice—either wild-type Gba or Gba —with letion, but were not rescueable. The patterns of lack of rescue of +/− + Gba2 mice. The mice were finally bred with Mx1–Cre mice certain cytokines in the double mutant may be due to the con- + −/− to yield Mx1–Cre :GD1:Gba2 mice. We have previously tinued elevation of GL-1 and LysoGL-1 (Fig. 4A), which might + fl/fl fl/− shown that Mx1–Cre :Gba and Mx1–Cre+:Gba mice have itself drive this hypercytokinemia. This GL1/LysoGL1 elevation is an identical clinical phenotype (4). Hence, these mutants were consistent with the persistence of Gaucher cells in the double pooled for the rescue studies.
Load more

Recommended publications
  • The Rise and Fall of the Bovine Corpus Luteum
    University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Spring 5-6-2017 The Rise and Fall of the Bovine Corpus Luteum Heather Talbott University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Biochemistry Commons, Molecular Biology Commons, and the Obstetrics and Gynecology Commons Recommended Citation Talbott, Heather, "The Rise and Fall of the Bovine Corpus Luteum" (2017). Theses & Dissertations. 207. https://digitalcommons.unmc.edu/etd/207 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. THE RISE AND FALL OF THE BOVINE CORPUS LUTEUM by Heather Talbott A DISSERTATION Presented to the Faculty of the University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Biochemistry and Molecular Biology Graduate Program Under the Supervision of Professor John S. Davis University of Nebraska Medical Center Omaha, Nebraska May, 2017 Supervisory Committee: Carol A. Casey, Ph.D. Andrea S. Cupp, Ph.D. Parmender P. Mehta, Ph.D. Justin L. Mott, Ph.D. i ACKNOWLEDGEMENTS This dissertation was supported by the Agriculture and Food Research Initiative from the USDA National Institute of Food and Agriculture (NIFA) Pre-doctoral award; University of Nebraska Medical Center Graduate Student Assistantship; University of Nebraska Medical Center Exceptional Incoming Graduate Student Award; the VA Nebraska-Western Iowa Health Care System Department of Veterans Affairs; and The Olson Center for Women’s Health, Department of Obstetrics and Gynecology, Nebraska Medical Center.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Molecular Reprogramming in Tomato Pollen During Development And
    Molecular reprogramming in tomato pollen during development and heat stress Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich Biowissenschaften (FB15) der Goethe-Universität Frankfurt am Main von Mario Keller geboren in Frankfurt am Main (Hessen) Frankfurt am Main 2018 (D30) Vom Fachbereich Biowissenschaften (FB15) der Goethe-Universität als Dissertation angenommen. Dekan: Prof. Dr. Sven Klimpel Gutachter: Prof. Dr. Enrico Schleiff, Jun. Prof. Dr. Michaela Müller-McNicoll Datum der Disputation: 25.03.2019 Index of contents Index of contents Index of contents ....................................................................................................................................... i Index of figures ........................................................................................................................................ iii Index of tables ......................................................................................................................................... iv Index of supplemental material ................................................................................................................ v Index of supplemental figures ............................................................................................................... v Index of supplemental tables ................................................................................................................ v Abbreviations ..........................................................................................................................................
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Glucocerebrosidase Mutations and Synucleinopathies. Potential Role of Sterylglucosides and Relevance of Studying Both GBA1 and GBA2 Genes
    MINI REVIEW published: 28 June 2018 doi: 10.3389/fnana.2018.00052 Glucocerebrosidase Mutations and Synucleinopathies. Potential Role of Sterylglucosides and Relevance of Studying Both GBA1 and GBA2 Genes Rafael Franco 1,2*†, Juan A. Sánchez-Arias 3†, Gemma Navarro 1,2,4 and José L. Lanciego 2,3,5* 1Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, Spain, 2Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain, 3Department of Neuroscience, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain, 4Department of Biochemistry and Physiology, School of Pharmacy, University of Barcelona, Barcelona, Spain, 5Department of Neuroscience, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain Gaucher’s disease (GD) is the most prevalent lysosomal storage disorder. GD is caused Edited by: by homozygous mutations of the GBA1 gene, which codes for beta-glucocerebrosidase Francesco Fornai, (GCase). Although GD primarily affects peripheral tissues, the presence of neurological Università degli Studi di Pisa, Italy symptoms has been reported in several GD subtypes. GBA1 mutations have Reviewed by: Rosario Moratalla, recently deserved increased attention upon the demonstration that both homo- and Consejo Superior de Investigaciones heterozygous GBA1 mutations represent the most important genetic risk factor for the Científicas (CSIC), Spain Fabrizio Michetti, appearance of synucleinopathies like Parkinson’s disease (PD) and dementia with Lewy Università Cattolica del Sacro Cuore, bodies (LBD). Although reduced GCase activity leads to alpha-synuclein aggregation, Italy the mechanisms sustaining a role for GCase in alpha-synuclein homeostasis still *Correspondence: Rafael Franco remain largely unknown.
    [Show full text]
  • Lucerastat, an Iminosugar with Potential As Substrate Reduction Therapy for Glycolipid Storage Disorders: Safety, Tolerability
    Guérard et al. Orphanet Journal of Rare Diseases (2017) 12:9 DOI 10.1186/s13023-017-0565-9 RESEARCH Open Access Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects N. Guérard1*, O. Morand2 and J. Dingemanse1 Abstract Background: Lucerastat, an inhibitor of glucosylceramide synthase, has the potential to restore the balance between synthesis and degradation of glycosphingolipids in glycolipid storage disorders such as Gaucher disease and Fabry disease. The safety, tolerability, and pharmacokinetics of oral lucerastat were evaluated in two separate randomized, double-blind, placebo-controlled, single- and multiple-ascending dose studies (SAD and MAD, respectively) in healthy male subjects. Methods: In the SAD study, 31 subjects received placebo or a single oral dose of 100, 300, 500, or 1000 mg lucerastat. Eight additional subjects received two doses of 1000 mg lucerastat or placebo separated by 12 h. In the MAD study, 37 subjects received placebo or 200, 500, or 1000 mg b.i.d. lucerastat for 7 consecutive days. Six subjects in the 500 mg cohort received lucerastat in both absence and presence of food. Results: In the SAD study, 15 adverse events (AEs) were reported in ten subjects. Eighteen AEs were reported in 15 subjects in the MAD study, in which the 500 mg dose cohort was repeated because of elevated alanine aminotransferase (ALT) values in 4 subjects, not observed in other dose cohorts. No severe or serious AE was observed. No clinically relevant abnormalities regarding vital signs and 12–lead electrocardiograms were observed. Lucerastat Cmax values were comparable between studies, with geometric mean Cmax 10.5 (95% CI: 7.5, 14.7) and 11.1 (95% CI: 8.7, 14.2) μg/mL in the SAD and MAD study, respectively, after 1000 mg lucerastat b.i.d.
    [Show full text]
  • The Design, Synthesis and Enzymatic Evaluation of Aminocyclitol Inhibitors of Glucocerebrosidase
    Lakehead University Knowledge Commons,http://knowledgecommons.lakeheadu.ca Electronic Theses and Dissertations Electronic Theses and Dissertations from 2009 2014-01-22 The design, synthesis and enzymatic evaluation of aminocyclitol inhibitors of glucocerebrosidase Adams, Benjamin Tyler http://knowledgecommons.lakeheadu.ca/handle/2453/478 Downloaded from Lakehead University, KnowledgeCommons THE DESIGN, SYNTHESIS AND ENZYMATIC EVALUATION OF AMINOCYCLITOL INHIBITORS OF GLUCOCEREBROSIDASE By Benjamin Tyler Adams A Thesis submitted to The Department of Chemistry Faculty of Science and Environmental Studies Lakehead University In partial fulfillment of the requirements for the degree of Master of Science August 2013 © Benjamin Tyler Adams, 2013 i Abstract Gaucher disease, the most common lysosomal storage disorder, is caused by mutations in the GBA gene which codes for the enzyme glucocerebrosidase (GCase) resulting in its deficiency. GCase deficiency results in the accumulation of its substrate glucosylceramide (GlcCer) within the lysosomes leading to various severities of hepatosplenomegaly, bone disease and neurodegeneration. For most forms of Gaucher disease, the mutations in the GBA gene cause the enzyme to misfold but retain catalytic activity. However, the misfolded mutant enzyme is recognized and degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway prior to delivery into the lysosome. Symptoms begin to show in patients when the function of the defective enzyme drops below 10-20% residual enzyme activity. There are currently three therapeutic approaches to treat Gaucher disease: enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and a relatively recent addition, enzyme enhancement therapy (EET) through the use of pharmacological chaperones. Many pharmacological chaperones are competitive inhibitors that are capable of enhancing lysosomal GCase activity by stabilizing the folded conformation of GCase enabling it to bypass the ERAD pathway.
    [Show full text]
  • Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses
    551 38 Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses Marie T. Vanier, Catherine Caillaud, Thierry Levade 38.1 Disorders of Sphingolipid Synthesis – 553 38.2 Sphingolipidoses – 556 38.3 Niemann-Pick Disease Type C – 566 38.4 Neuronal Ceroid Lipofuscinoses – 568 References – 571 J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases, DOI 10.1007/978-3-662-49771-5_ 38 , © Springer-Verlag Berlin Heidelberg 2016 552 Chapter 38 · Disor ders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses O C 22:0 (Fatty acid) Ganglio- series a series b HN OH Sphingosine (Sphingoid base) OH βββ β βββ β Typical Ceramide (Cer) -Cer -Cer GD1a GT1b Glc ββββ βββ β Gal -Cer -Cer Globo-series GalNAc GM1a GD1b Neu5Ac βαββ -Cer Gb4 ββ β ββ β -Cer -Cer αβ β -Cer GM2 GD2 Sphingomyelin Pcholine-Cer Gb3 B4GALNT1 [SPG46] [SPG26] β β β ββ ββ CERS1-6 GBA2 -Cer -Cer ST3GAL5 -Cer -Cer So1P So Cer GM3 GD3 GlcCer - LacCer UDP-Glc UDP Gal CMP -Neu5Ac - UDP Gal PAPS Glycosphingolipids GalCer Sulfatide ββ Dihydro -Cer -Cer SO 4 Golgi Ceramide apparatus 2-OH- 2-OH-FA Acyl-CoA FA2H CERS1-6 [SPG35] CYP4F22 ω-OH- ω-OH- FA Acyl-CoA ULCFA ULCFA-CoA ULCFA GM1, GM2, GM3: monosialo- Sphinganine gangliosides Endoplasmic GD3, GD2, GD1a, GD1b: disialo-gangliosides reticulum KetoSphinganine GT1b: trisialoganglioside SPTLC1/2 [HSAN1] N-acetyl-neuraminic acid: sialic acid found in normal human cells Palmitoyl-CoA Deoxy-sphinganine + Serine +Ala or Gly Deoxymethylsphinganine 38 . Fig. 38.1 Schematic representation of the structure of the main sphingolipids , and their biosynthetic pathways.
    [Show full text]
  • Activity-Based Inhibitors of Glycosidases: Design and Applications
    UvA-DARE (Digital Academic Repository) Activity-based probes for retaining β-glucosidases: Novel tools for research and diagnostics Kallemeijn, W.W. Publication date 2014 Link to publication Citation for published version (APA): Kallemeijn, W. W. (2014). Activity-based probes for retaining β-glucosidases: Novel tools for research and diagnostics. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:06 Oct 2021 Introduction, part I Activity-based inhibitors of glycosidases: Design and applications Wouter W. Kallemeijna, Martin D. Witteb, Tom Wennekesc, Johannes M. F. G. Aertsa and Hermen S. Overkleeftd Prepared as invited review in Advances in Carbohydrate Chemistry and Biochemistry. Graphical abstract – An activity-based probe can bind a target enzyme through mimicry of its substrate, form a covalent bond with the target via its catalytic mechanism, and allows detection of the bound enzyme by the implementation of a reporter tag.
    [Show full text]
  • Glucocerebrosidase: Functions in and Beyond the Lysosome
    Journal of Clinical Medicine Review Glucocerebrosidase: Functions in and Beyond the Lysosome Daphne E.C. Boer 1, Jeroen van Smeden 2,3, Joke A. Bouwstra 2 and Johannes M.F.G Aerts 1,* 1 Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, Faculty of Science, 2333 CC Leiden, The Netherlands; [email protected] 2 Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Faculty of Science, 2333 CC Leiden, The Netherlands; [email protected] (J.v.S.); [email protected] (J.A.B.) 3 Centre for Human Drug Research, 2333 CL Leiden, The Netherlands * Correspondence: [email protected] Received: 29 January 2020; Accepted: 4 March 2020; Published: 9 March 2020 Abstract: Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes. Crucially, GCase generates ceramides from GlcCer molecules in the outer part of the skin, a process essential for optimal skin barrier property and survival. This review covers the functions of GCase in and beyond lysosomes and also pays attention to the increasing insight in hitherto unexpected catalytic versatility of the enzyme. Keywords: glucocerebrosidase; lysosome; glucosylceramide; skin; Gaucher disease 1.
    [Show full text]
  • Lysosomal Enzyme Activities As Possible CSF Biomarkers Of
    Clinica Chimica Acta 495 (2019) 13–24 Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/cca Lysosomal enzyme activities as possible CSF biomarkers of synucleinopathies T ⁎ Silvia Paciottia,b, , Leonardo Gatticchia, Tommaso Beccaric, Lucilla Parnettib a Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Perugia, Italy b Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy c Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy ARTICLE INFO ABSTRACT Keywords: Mutations on the GBA gene, encoding for the lysosomal enzyme β-glucocerebrosidase (GCase), have been Lysosomal enzyme activity identified as the most common genetic risk factor involved in the development of Parkinson's disease (PD) and Cerebrospinal fluid dementia with Lewy bodies (DLB), indicating a direct contribution of this enzyme to the pathogenesis of sy- β -glucocerebrosidase nucleinopathies. Parkinson's disease Decreased GCase activity has been observed repeatedly in brain tissues and biological fluids of both GBA Synucleinopathies mutation carrier and non-carrier PD and DLB patients, suggesting that lower GCase activity constitutes a typical GBA feature of these disorders. Additional genetic, pathological and biochemical data on other lysosomal enzymes (e.g., Acid sphingomye- linase, Cathepsin D, α-galactosidase A and β-hexosaminidase) have further strengthened the evidence of a link between lysosomal dysfunction and synucleinopathies. A few studies have been performed for assessing the potential value of lysosomal enzyme activities in cere- brospinal fluid (CSF) as biomarkers for synucleinopathies. The reduction of GCase activity in the CSF of PD and DLB patients was validated in several of them, whereas the behaviour of other lysosomal enzyme activities was not consistently reliable among the studies.
    [Show full text]
  • Modulates Plant Cell-Wall Composition
    Arabidopsis Response Regulator 6 (ARR6) Modulates Plant Cell-Wall Composition and Disease Resistance Laura Bacete, Hugo Mélida, Gemma López, Patrick Dabos, Dominique Tremousaygue, Nicolas Denancé, Eva Miedes, Vincent Bulone, Deborah Goffner, Antonio Molina To cite this version: Laura Bacete, Hugo Mélida, Gemma López, Patrick Dabos, Dominique Tremousaygue, et al.. Ara- bidopsis Response Regulator 6 (ARR6) Modulates Plant Cell-Wall Composition and Disease Re- sistance. Molecular Plant-Microbe Interactions, American Phytopathological Society, 2020, 33 (5), pp.767-780. 10.1094/MPMI-12-19-0341-R. hal-03023355 HAL Id: hal-03023355 https://hal.archives-ouvertes.fr/hal-03023355 Submitted on 27 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Page 1 of 119 Molecular Plant-Microbe Interactions Laura Bacete et al. 1 Arabidopsis Response Regulator 6 (ARR6) modulates plant 2 cell wall composition and disease resistance 3 Laura Bacete1,2,#, Hugo Mélida1, Gemma López1, Patrick Dabos3, Dominique 4 Tremousaygue3, Nicolas Denancé3,4,†, Eva Miedes1,2, Vincent Bulone5,6, Deborah 5 Goffner4, and Antonio Molina1,2* 6 1Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid 7 (UPM)-Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), 8 Campus Montegancedo-UPM, 28223-Pozuelo de Alarcón (Madrid), Spain.
    [Show full text]