DOCSLIB.ORG

Sphingolipid Metabolism Diseases ⁎ Thomas Kolter, Konrad Sandhoff

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Sphingolipid Metabolism Diseases ⁎ Thomas Kolter, Konrad Sandhoff View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1758 (2006) 2057–2079 www.elsevier.com/locate/bbamem Review Sphingolipid metabolism diseases ⁎ Thomas Kolter, Konrad Sandhoff Kekulé-Institut für Organische Chemie und Biochemie der Universität, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany Received 23 December 2005; received in revised form 26 April 2006; accepted 23 May 2006 Available online 14 June 2006 Abstract Human diseases caused by alterations in the metabolism of sphingolipids or glycosphingolipids are mainly disorders of the degradation of these compounds. The sphingolipidoses are a group of monogenic inherited diseases caused by defects in the system of lysosomal sphingolipid degradation, with subsequent accumulation of non-degradable storage material in one or more organs. Most sphingolipidoses are associated with high mortality. Both, the ratio of substrate influx into the lysosomes and the reduced degradative capacity can be addressed by therapeutic approaches. In addition to symptomatic treatments, the current strategies for restoration of the reduced substrate degradation within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated “cross correction”, gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate reduction therapy. Patients suffering from the attenuated form (type 1) of Gaucher disease and from Fabry disease have been successfully treated with ERT. © 2006 Elsevier B.V. All rights reserved. Keywords: Ceramide; Lysosomal storage disease; Saposin; Sphingolipidose Contents 1. Sphingolipid structure, function and biosynthesis ..........................................2058 1.1. Less precisely defined is the role of sphingolipids in cancer [25]. ............................2058 1.2. Biosynthesis ..........................................................2058 2. Glycosphingolipid catabolism ....................................................2059 2.1. Topology ...........................................................2060 2.2. Sphingolipid activator proteins ................................................2060 2.3. Intralysosomal membranes ..................................................2060 3. Sphingolipidoses ...........................................................2062 3.1. GM1-gangliosidosis ......................................................2062 3.2. GM2-gangliosidoses ......................................................2063 3.3. Tay–Sachs disease.......................................................2063 3.4. Sandhoff disease........................................................2063 3.5. AB-variant of GM2-gangliosidosis ..............................................2064 3.6. Fabry disease .........................................................2064 3.7. Gaucher disease ........................................................2064 3.8. Metachromatic leukodystrophy ................................................2065 3.9. Krabbe disease ........................................................2066 3.10. Niemann–Pick disease, type A and B .............................................2067 3.11. Farber disease .........................................................2067 ⁎ Corresponding author. Tel.: +49 228 73 53 46; fax: +49 228 73 77 78. E-mail addresses: [email protected] (T. Kolter), [email protected] (K. Sandhoff). 0005-2736/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamem.2006.05.027 2058 T. Kolter, K. Sandhoff / Biochimica et Biophysica Acta 1758 (2006) 2057–2079 3.12. Deficiency of Saposins (Saps) ............................................... 2068 3.12.1. Prosaposin .................................................... 2068 3.12.2. Sap-A....................................................... 2068 3.12.3. Sap-B deficiency ................................................. 2068 3.12.4. Sap-C deficiency ................................................. 2068 3.12.5. Sap-D....................................................... 2068 4. Pathogenesis of spingolipidoses ................................................... 2069 5. Diagnosis .............................................................. 2070 6. Therapeutic approaches ....................................................... 2070 6.1. Enzyme replacement therapy (ERT) ............................................. 2070 6.2. Cell-mediated therapy (CMT) ................................................ 2070 6.3. Gene therapy ......................................................... 2070 6.4. Enzyme-enhancement therapy ................................................ 2071 6.5. Substrate reduction therapy (SRT) .............................................. 2071 Acknowledgements ............................................................ 2071 References ................................................................ 2071 1. Sphingolipid structure, function and biosynthesis [32]; for example, the highly immunogenic, non-human α- galactosylphytoceramide activates a subset of NKT cells. This Together with glycerophospholipids and cholesterol, sphin- glycosphingolipid from the marine sponge Agelas mauritianus golipids are building blocks of eukaryotic membranes. They are [21] has gained much interest as a potential drug in the treatment characterized by the presence of a sphingoid base within the of cancer and autoimmune diseases [22,23]. An endogenous hydrophobic part of the molecule. In sphingomyelin and the sphingolipid ligand for CD1d and important for the maturation glycosphingolipids, a phosphorylcholine or a carbohydrate of NKT-cells appears to be isoglobotriaosylceramide. This was moiety are bound to the terminal hydroxyl group of ceramide demonstrated by a deficiency of invariant NKT-cells in β- (N-acylsphingosine), respectively (Fig. 1) [1]. hexosaminidase B-deficient mice, the animal model of Sandhoff Glycosphingolipids display a high structural diversity and diseases, which cannot convert isoglobotetraosylceramide into can be classified into series, which are characteristic for a group isoglobotriaosylceramide [24]. of evolutionary related organisms [1]. On cellular surfaces, glycosphingolipids form characteristic patterns that are species- 1.1. Less precisely defined is the role of sphingolipids in cancer and cell-type specific and change with cell growth, differentia- [25] tion, viral transformation, ontogenesis, and oncogenesis [2].In the plasma membrane, they are believed to segregate into pre- Intermediates of sphingolipid metabolism appear to be existing microdomains [3,4], which are enriched in glycosyl- involved in the transduction of extracellular signals into the phosphatidylinositol-anchored proteins, sphingomyelin, and interior of cells. Ceramide can be released from sphingomyelin or cholesterol. These so-called lipid rafts [5,6] might constitute by de-novo synthesis in response to substances like vitamin D3, the physiological surroundings of many membrane proteins. tumor necrosis factor α, γ-interferon, or interleukin 1. In most cell Glycosphingolipids are essential for development and types, ceramide mediates antimitogenic responses such as cell survival of multicellular organisms [7]; they play a role in cell differentiation, cell cycle arrest, cell senescence or apoptosis [26]. adhesion phenomena [8,9] and in the regulation of membrane Also other intermediates of sphingolipid metabolism such as proteins. Thus, absence of ganglioside GM3 in vivo leads to sphingosine, sphingosylphosphorylcholine [27], sphingosine-1- enhanced insulin receptor phosphorylation and increased insulin phosphate and ceramide-1-phosphate [28,29], are regarded as sensitivity [10]. Correct sphingolipid processing is also vital for signalling substances. Accordingly, the benefit of pharmacologi- the barrier function of the human skin [11], where ceramides of cal interference with sphingolipid-mediated processes has been the stratum corneum contribute to the water permeability barrier. investigated for several diseases [30,31]. Skin ceramides occur in free form [12], or covalently linked to Not only sphingolipids–including the signalling substances proteins of the cornified envelope [13]. In addition to disorders sphingosine-1-phosphate and ceramide–contribute to many phy- caused by alterations of sphingolipid metabolism, sphingolipids siological and pathological processes, but also the proteins are involved in a variety of diseases [14]. In infectious diseases, operating in the sphingolipid pathway can serve different functions. sphingolipids serve, e.g., as pathogen receptors [15–17] and can For example, sphingolipid activator proteins are required for the control pathogen infection and host defense [18]. In the immune presentation of lipid antigens to CD1 molecules [32]. system, glycosphingolipids play a role as antigens (ABO- System, Forssman), but can also stimulate the generation of 1.2. Biosynthesis autoantibodies in postinfectious autoimmune diseases like Guillain–Barré or Miller–Fisher Syndromes [19,20]. They are The first steps of glycosphingolipid biosynthesis lead to the ligands for CD1d-restricted natural killer T-cells (NKT-cells) formation of ceramide at the cytoplasmic face of the ER T. Kolter, K. Sandhoff / Biochimica et Biophysica Acta 1758 (2006) 2057–2079 2059 Fig. 1. Structures of ganglioside GM2, bis(monoacylglycero)phosphate
Load more

Recommended publications
  • From Genes to Systems: New Global Strategies for the Characterization of NCL Biology ⁎ Anu Jalanko A, , Jaana Tyynelä B, Leena Peltonen A,C,D,E
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1762 (2006) 934–944 www.elsevier.com/locate/bbadis Review From genes to systems: New global strategies for the characterization of NCL biology ⁎ Anu Jalanko a, , Jaana Tyynelä b, Leena Peltonen a,c,d,e a National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, P.O. Box 104, 00251 Helsinki, Finland b University of Helsinki, Institute of Biomedicine/Biochemistry, Finland c University of Helsinki, Department of Medical Genetics, Finland d Research Programme of Molecular Medicine and Research Programme of Neurosciences, Biomedicum Helsinki, Finland e The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Received 22 April 2006; received in revised form 1 September 2006; accepted 5 September 2006 Available online 12 September 2006 Abstract Neuronal ceroid lipofuscinoses (NCL) are rare neurological disorders with a uniform phenotype, caused by mutations in seven known genes. NCL provide a unique model to characterize molecular pathways critical for normal neuronal development and pathological neuronal degeneration. Systems biology based approach utilizes the rapidly developing tools of genomics, proteomics, lipidomics and metabolomics and aims at thorough understanding of the functions of cells, tissues and whole organisms by molecular analysis and biocomputing-assisted modeling. The systems level understanding of NCL is now possible by utilizing different model organisms. Initial work has revealed disturbed metabolic pathways in several NCL disorders and most analyses have utilized the infantile (INCL/CLN1) and juvenile (JNCL/CLN3) disease modeling and utilized mainly human and mouse samples.
    [Show full text]
  • The Neutral Glycosphingolipid Globotriaosylceramide Promotes Fusion Mediated by a CD4-Dependent CXCR4-Utilizing HIV Type 1 Envelope Glycoprotein
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 14435–14440, November 1998 Medical Sciences The neutral glycosphingolipid globotriaosylceramide promotes fusion mediated by a CD4-dependent CXCR4-utilizing HIV type 1 envelope glycoprotein ANU PURI*, PETER HUG*, KRISTINE JERNIGAN*, JOSEPH BARCHI†,HEE-YONG KIM‡,JILLON HAMILTON‡, i JOE¨LLE WIELS§,GARY J. MURRAY¶,ROSCOE O. BRADY¶, AND ROBERT BLUMENTHAL* *Section of Membrane Structure and Function, Laboratory of Experimental and Computational Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; †Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute and ¶Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; ‡Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852; and §Centre National de la Recherche Scientifique Unite´Mixte de Recherche 1598, Institut Gustave Roussy, Villejuif Cedex 94805, France Contributed by Roscoe O. Brady, September 25, 1998 ABSTRACT Previously, we showed that the addition of enabling individual HIV strains to choose between alternate human erythrocyte glycosphingolipids (GSLs) to nonhuman modes of entry into cells. CD41 or GSL-depleted human CD41 cells rendered those cells The GSL hypothesis is based on a number of observations, susceptible to HIV-1 envelope glycoprotein-mediated cell fu- including recovery of fusion of nonsusceptible cells after sion. Individual components in the GSL mixture were isolated transfer of protease- and heat-resistant components from by fractionation on a silica-gel column and incorporated into human erythrocytes (12, 13), physicochemical studies on the the membranes of CD41 cells.
    [Show full text]
  • Management of Patients with Cardiac Manifestations
    MANAGEMENT OF PATIENTS WITH CARDIAC MANIFESTATIONS KDIGOAleš Linhart First School of Medicine Charles University Prague Czech Republic Disclosure of Interests Speaker´s honoraria, travel reimbursements and consultancy honoraria from: • Genzyme • Shire HGT • Amicus Therapeutics • Actelion KDIGO KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland KDIGO HEART FAILURE KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland Diffuse LVH on MRI in Fabry disease KDIGO KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland Data source: General University Hospital, Prague Cardiac symptoms in AFD LV hypertrophy absent LV hypertrophy present KDIGO KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland Linhart et al., European Heart Journal 2007 28(10):1228-1235 Fabry left ventricular function KDIGO KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland N-Terminal Pro-BNP in Diagnosis of Cardiac Involvement in AFD Patients 117 patients, (age 48 ± 15 years, 46.2% men) - BNP elevated in 57% KDIGO KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland Coats et al., Am J Cardiol. 2013;111:111-7. Diagnosis of heart failure KDIGO ESC GuidelinesKDIGO Controversies for the Conference diagnosis on Fabry and Disease treatment | October of 15-17, acute 2015 and | Dublin, chronic Ireland heart failure 2012. European Heart Journal 2012; 33: 1787–1847 Trials in heart failure with preserved ejection fraction DIG-PEF Digoxin Trend to ↓ hospitalizations ↑ UAP CHARM-PRESERVED Candesartan Trend ↓ hospitalizations I-PRESERVE Irbesartan No effect PEP-CHF PerindoprilKDIGO↓ hospitalizations SENIORS HF-PEF Nebivolol Trend to ↓ Clinical subgroup complications TOP-CAT Spironolactone Effective in subjects recruited in USA and LATAM KDIGO Controversies Conference on Fabry Disease | October 15-17, 2015 | Dublin, Ireland J Am Coll Cardiol.
    [Show full text]
  • Attenuation of Ganglioside GM1 Accumulation in the Brain of GM1 Gangliosidosis Mice by Neonatal Intravenous Gene Transfer
    Gene Therapy (2003) 10, 1487–1493 & 2003 Nature Publishing Group All rights reserved 0969-7128/03 $25.00 www.nature.com/gt RESEARCH ARTICLE Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer N Takaura1, T Yagi2, M Maeda2, E Nanba3, A Oshima4, Y Suzuki5, T Yamano1 and A Tanaka1 1Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan; 2Department of Neurobiology and Anatomy, Osaka City University Graduate School of Medicine, Osaka, Japan; 3Gene Research Center, Tottori University, Yonago, Japan; 4Department of Pediatrics, Takagi Hospital, Saitama, Japan; and 5Pediatrics, Clinical Research Center, Nasu Institute for Developmental Disabilities, International University of Health and Welfare, Ohtawara, Japan A single intravenous injection with 4 Â 107 PFU of recombi- ganglioside GM1 was above the normal range in all treated nant adenovirus encoding mouse b-galactosidase cDNA to mice, which was speculated to be the result of reaccumula- newborn mice provided widespread increases of b-galacto- tion. However, the values were still definitely lower in most of sidase activity, and attenuated the development of the the treated mice than those in untreated mice. In the disease including the brain at least for 60 days. The b- histopathological study, X-gal-positive cells, which showed galactosidase activity showed 2–4 times as high a normal the expression of exogenous b-galactosidase gene, were activity in the liver and lung, and 50 times in the heart. In the observed in the brain. It is noteworthy that neonatal brain, while the activity was only 10–20% of normal, the administration via blood vessels provided access to the efficacy of the treatment was distinct.
    [Show full text]
  • N-Acetyl-L-Leucine Improves Functional Recovery and Attenuates Cortical Cell
    www.nature.com/scientificreports OPEN N‑Acetyl‑l‑leucine improves functional recovery and attenuates cortical cell death and neuroinfammation after traumatic brain injury in mice Nivedita Hegdekar1, Marta M. Lipinski1,2* & Chinmoy Sarkar1* Traumatic brain injury (TBI) is a major cause of mortality and long‑term disability around the world. Even mild to moderate TBI can lead to lifelong neurological impairment due to acute and progressive neurodegeneration and neuroinfammation induced by the injury. Thus, the discovery of novel treatments which can be used as early therapeutic interventions following TBI is essential to restrict neuronal cell death and neuroinfammation. We demonstrate that orally administered N‑acetyl‑l‑ leucine (NALL) signifcantly improved motor and cognitive outcomes in the injured mice, led to the attenuation of cell death, and reduced the expression of neuroinfammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice. Our data indicate that partial restoration of autophagy fux mediated by NALL may account for the positive efect of treatment in the injured mouse brain. Taken together, our study indicates that treatment with NALL would be expected to improve neurological function after injury by restricting cortical cell death and neuroinfammation. Therefore, NALL is a promising novel, neuroprotective drug candidate for the treatment of TBI. Traumatic brain injury (TBI) is a major health concern all over the world. Between 1990 and 2016, the prevalence of TBI increased by around 8.4%1. Almost 27 million new cases of TBI were reported worldwide in 2016, with an incidence rate of 369 per 100,000 people 1. In the US around 1.7 million cases of TBI are reported each year 2,3.
    [Show full text]
  • Characterization of a Mutation in a Family with Saposin B Deficiency
    Proc. Nadl. Acad. Sci. USA Vol. 87, pp. 2541-2544, April 1990 Genetics Characterization of a mutation in a family with saposin B deficiency: A glycosylation site defect (sphingolipid activator protein/SAP-1/metachromatic leukodystrophy/arylsulfatase A) KEITH A. KRETZ*, GEOFFREY S. CARSON*, SATOSHI MORIMOTO*t, YASUO KISHIMOTO*, ARVAN L. FLUHARTYt, AND JOHN S. O'BPUEN*§ *Department of Neurosciences and Center for Molecular Genetics, University of California, San Diego, School of Medicine, M-034J, La Jolla, CA 92093; and tUniversity of California, Los Angeles, Mental Retardation Research Center Group at Lanterman Developmental Center, Pomona, CA 91766 Communicated by Dan L. Lindsley, January 19, 1990 ABSTRACT Saposins are small, heat-stable glycoproteins these four saposin proteins has now been isolated and their required for the hydrolysis of sphingolipids by specific lyso- activating properties have been determined (3-14). somal hydrolases. Saposins A, B, C, and D are derived by Saposins A and C specifically activate hydrolysis of glu- proteolytic processing from a single precursor protein named cocerebroside byB-glucosylceramidase (D-glucosyl-N-acyl- prosaposin. Saposin B, previously known as SAP-1 and sul- sphingosine glucohydrolase; EC 3.2.1.45) and ofgalactocere- fatide activator, stimulates the hydrolysis of a wide variety of broside by galactosylceramidase (D-galactosyl-N-acyl- substrates including cerebroside sulfate, GM1 ganglioside, and sphingosine galactohydrolase; EC 3.2.1.46) (3, 4). Saposin D globotriaosylceramide by arylsulfatase A, acid 8-galacto- specifically activates the hydrolysis of sphingomyelin by sidase, and a-galactosidase, respectively. Human saposin B sphingomyelin phosphodiesterase (sphingomyelin choline- deficiency, transmitted as an autosomal recessive trait, results phosphohydrolase; EC 3.1.4.12) (5).
    [Show full text]
  • Structural Evidence for Adaptive Ligand Binding of Glycolipid Transfer Protein
    doi:10.1016/j.jmb.2005.10.031 J. Mol. Biol. (2006) 355, 224–236 Structural Evidence for Adaptive Ligand Binding of Glycolipid Transfer Protein Tomi T. Airenne†, Heidi Kidron†, Yvonne Nymalm, Matts Nylund Gun West, Peter Mattjus and Tiina A. Salminen* Department of Biochemistry Glycolipids participate in many important cellular processes and they are and Pharmacy, A˚ bo Akademi bound and transferred with high specificity by glycolipid transfer protein University, Tykisto¨katu 6A (GLTP). We have solved three different X-ray structures of bovine GLTP at FIN-20520 Turku, Finland 1.4 A˚ , 1.6 A˚ and 1.8 A˚ resolution, all with a bound fatty acid or glycolipid. The 1.4 A˚ structure resembles the recently characterized apo-form of the human GLTP but the other two structures represent an intermediate conformation of the apo-GLTPs and the human lactosylceramide-bound GLTP structure. These novel structures give insight into the mechanism of lipid binding and how GLTP may conformationally adapt to different lipids. Furthermore, based on the structural comparison of the GLTP structures and the three-dimensional models of the related Podospora anserina HET-C2 and Arabidopsis thaliana accelerated cell death protein, ACD11, we give structural explanations for their specific lipid binding properties. q 2005 Elsevier Ltd. All rights reserved. Keywords: crystal structure; homology modeling; conformational change; *Corresponding author cavity; fluorescence Introduction to the diverse roles of glycolipids in the cell, GLTP could potentially function as a modulator
    [Show full text]
  • Genetic Ablation of Acid Ceramidase in Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target
    Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target Yedda Lia, Yue Xub, Bruno A. Beniteza, Murtaza S. Nagreec, Joshua T. Dearborna, Xuntian Jianga, Miguel A. Guzmand, Josh C. Woloszynekb, Alex Giaramitab, Bryan K. Yipb, Joseph Elsberndb, Michael C. Babcockb, Melanie Lob, Stephen C. Fowlere, David F. Wozniakf, Carole A. Voglerd, Jeffrey A. Medinc,g, Brett E. Crawfordb, and Mark S. Sandsa,h,1 aDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110; bDepartment of Research, BioMarin Pharmaceutical Inc., Novato, CA 94949; cDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada; dDepartment of Pathology, St. Louis University School of Medicine, St. Louis, MO 63104; eDepartment of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045; fDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110; gPediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226; and hDepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110 Edited by William S. Sly, Saint Louis University School of Medicine, St. Louis, MO, and approved August 16, 2019 (received for review July 15, 2019) Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a generated catabolically through the deacylation of galactosylceramide fatal demyelinating disorder caused by a deficiency in the lyso- by acid ceramidase (ACDase). This effectively dissociates GALC somal enzyme galactosylceramidase (GALC). GALC deficiency leads deficiency from psychosine accumulation, allowing us to test the to the accumulation of the cytotoxic glycolipid, galactosylsphingosine long-standing psychosine hypothesis. We demonstrate that genetic (psychosine). Complementary evidence suggested that psychosine loss of ACDase activity [Farber disease (FD) (8)] in the twitcher is synthesized via an anabolic pathway.
    [Show full text]
  • The Multiple Roles of Sphingomyelin in Parkinson's Disease
    biomolecules Review The Multiple Roles of Sphingomyelin in Parkinson’s Disease Paola Signorelli 1 , Carmela Conte 2 and Elisabetta Albi 2,* 1 Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, 20142 Milan, Italy; [email protected] 2 Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy; [email protected] * Correspondence: [email protected] Abstract: Advances over the past decade have improved our understanding of the role of sphin- golipid in the onset and progression of Parkinson’s disease. Much attention has been paid to ceramide derived molecules, especially glucocerebroside, and little on sphingomyelin, a critical molecule for brain physiopathology. Sphingomyelin has been proposed to be involved in PD due to its presence in the myelin sheath and for its role in nerve impulse transmission, in presynaptic plasticity, and in neurotransmitter receptor localization. The analysis of sphingomyelin-metabolizing enzymes, the development of specific inhibitors, and advanced mass spectrometry have all provided insight into the signaling mechanisms of sphingomyelin and its implications in Parkinson’s disease. This review describes in vitro and in vivo studies with often conflicting results. We focus on the synthesis and degradation enzymes of sphingomyelin, highlighting the genetic risks and the molecular alterations associated with Parkinson’s disease. Keywords: sphingomyelin; sphingolipids; Parkinson’s disease; neurodegeneration Citation: Signorelli, P.; Conte, C.; 1. Introduction Albi, E. The Multiple Roles of Sphingomyelin in Parkinson’s Parkinson’s disease (PD) is the second most common neurodegenerative disease (ND) Disease. Biomolecules 2021, 11, 1311. after Alzheimer’s disease (AD). Recent breakthroughs in our knowledge of the molecular https://doi.org/10.3390/ mechanisms underlying PD involve unfolded protein responses and protein aggregation.
    [Show full text]
  • Sphingolipids and Cell Signaling: Relationship Between Health and Disease in the Central Nervous System
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 April 2021 doi:10.20944/preprints202104.0161.v1 Review Sphingolipids and cell signaling: Relationship between health and disease in the central nervous system Andrés Felipe Leal1, Diego A. Suarez1,2, Olga Yaneth Echeverri-Peña1, Sonia Luz Albarracín3, Carlos Javier Alméciga-Díaz1*, Angela Johana Espejo-Mojica1* 1 Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., 110231, Colombia; [email protected] (A.F.L.), [email protected] (D.A.S.), [email protected] (O.Y.E.P.) 2 Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C., Colombia; [email protected] (D.A.S.) 3 Nutrition and Biochemistry Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; [email protected] (S.L.A.) * Correspondence: [email protected]; Tel.: +57-1-3208320 (Ext 4140) (C.J.A-D.). [email protected]; Tel.: +57-1-3208320 (Ext 4099) (A.J.E.M.) Abstract Sphingolipids are lipids derived from an 18-carbons unsaturated amino alcohol, the sphingosine. Ceramide, sphingomyelins, sphingosine-1-phosphates, gangliosides and globosides, are part of this group of lipids that participate in important cellular roles such as structural part of plasmatic and organelle membranes maintaining their function and integrity, cell signaling response, cell growth, cell cycle, cell death, inflammation, cell migration and differentiation, autophagy, angiogenesis, immune system. The metabolism of these lipids involves a broad and complex network of reactions that convert one lipid into others through different specialized enzymes. Impairment of sphingolipids metabolism has been associated with several disorders, from several lysosomal storage diseases, known as sphingolipidoses, to polygenic diseases such as diabetes and Parkinson and Alzheimer diseases.
    [Show full text]
  • Occurrence of Sulfatide As a Major Glycosphingolipid in WHHL Rabbit Serum Lipoproteins1
    J. Biochem. 102, 83-92 (1987) Occurrence of Sulfatide as a Major Glycosphingolipid in WHHL Rabbit Serum Lipoproteins1 Atsushi HARA and Tamotsu TAKETOMI Department of Lipid Biochemistry, Institute of Cardiovascular Disease , Shinshu University School of Medicine, Matsumoto , Nagano 390 Received for publication, February 12, 1987 Glycosphingolipids in serum and lipoproteins from Watanabe hereditable hyper li pidemic rabbit (WHHL rabbit), which is an animal model for human familial hypercholesterolemia (FH), were analyzed for the first time in this study . Chylo microns and very low density, low density, and high density lipoproteins contained sulfatide as a major glycosphingolipid (12nmol/ƒÊmol total phospholipids (PL) in chylomicrons, 19nmol/ƒÊmol PL in VLDL, 18nmol/ƒÊmol PL in LDL, and 14nmol/ƒÊ mol PL in HDL) with other minor glycosphingolipids such as glucosylceramide, galactosylceramide, GM3 ganglioside, lactosylceramide, and globotriaosylceramide. The concentration of sulfatide as a major glycosphingolipid in WHHL rabbit serum (121nmol/ml) was much higher than that in normal rabbit serum (3nmol/ml). Fatty acids of the sulfatides comprised mainly nonhydroxy fatty acids (C22, 23, and 24) and significant amounts of hydroxy fatty acids (about 10%), whereas long chain bases of the sulfatides comprised mostly (4E)-sphingenine with a significant amount of 4D-hydroxysphinganine (about 10%). Furthermore, sulfatides in the liver and small intestine from normal and WHHL rabbits (where serum lipoproteins are produced) were determined to amount to 260nmol/g liver in WHHL rabbit, 104 nmol/g liver in control rabbit, 99.6nmol/g small intestine in WHHL rabbit, and 31.2nmol/g small intestine in control rabbit. Ceramide portions of the sulfatides in the liver were mainly composed of (4E)-sphingenine and nonhydroxy fatty acids, while those in the small intestine were mainly composed of 4D-hydroxysphinganine and hydroxy fatty acids.
    [Show full text]
  • GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
    International Journal of Molecular Sciences Review GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies Andrés Felipe Leal 1 , Eliana Benincore-Flórez 1, Daniela Solano-Galarza 1, Rafael Guillermo Garzón Jaramillo 1 , Olga Yaneth Echeverri-Peña 1, Diego A. Suarez 1,2, Carlos Javier Alméciga-Díaz 1,* and Angela Johana Espejo-Mojica 1,* 1 Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; [email protected] (A.F.L.); [email protected] (E.B.-F.); [email protected] (D.S.-G.); [email protected] (R.G.G.J.); [email protected] (O.Y.E.-P.); [email protected] (D.A.S.) 2 Faculty of Medicine, Universidad Nacional de Colombia, Bogotá 110231, Colombia * Correspondence: [email protected] (C.J.A.-D.); [email protected] (A.J.E.-M.); Tel.: +57-1-3208320 (ext. 4140) (C.J.A.-D.); +57-1-3208320 (ext. 4099) (A.J.E.-M.) Received: 6 July 2020; Accepted: 7 August 2020; Published: 27 August 2020 Abstract: GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy.
    [Show full text]