DOCSLIB.ORG

Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. Red arrows denote the defective pathways that are discussed in this chapter. The names of genes that are mutated are indicated. Cer, ceramide ; FA, fatty acid; Gal, galactose; GalCer, galactosylceramide ; GalNAc, N-acetyl-galactosamine ; Gb3, globotriaosylceramide ; Gb4, globo- tetraosylceramide (globoside ); Glc, glucose; GlcCer, glucosylceramide ; LacCer, lactosylceramide ; Neu5Ac, N-acetyl-neuraminic acid ; 2-OH-FA, 2-hydroxy-fatty acid; ω-OH-ULCFA, ω-hydroxy ultra-long chain fatty acid ; PAPS, 3’-phosphoadenosine-5’-phosphosulfate ; Pcholine, phosphorylcholine ; So, sphingosine ; So1P, sphingosine-1-phosphate. Solid bars indicate metabolic blocks Sphingolipid Structure and Metabolism Sphingolipids are ubiquitous lipids found (sphingosine being the prototype) that can phosphingolipids contain phosphoryl- in all mammalian cell membranes and in be N-acylated by a variety of fatty acids, choline (sphingomyelin), phosphoryle- plasma lipoproteins. Many exhibit dual forming ceramides (Cer) (. Fig. 38.1). thanolamine, or a phosphate group. functions, as key structural elements, but Depending on the type of hydrophilic Glycosphingolipids contain one (glucose also as modulators of numerous biologi- head group linked to the 1-OH group of or galactose) or several sugar residues, cal/physiological functions. Their back- the sphingoid base, two main classes of and can be very complex. Sialic acid bone is a long chain sphingoid base sphingolipids are distinguished. Phos- (N-acetyl-neuraminic acid in humans) 553 38 38.1 · Disorders of Sphingolipid Synthesis containing glycosphingolipids are named by the condensation of serine and palmi- leads to the formation of more complex gangliosides . Depending on the precise toyl-CoA, a reaction catalyzed by serine neutral glycosphingolipids and ganglio- structure (sugar and linkage) of the oligo- palmitoyltransferase . The resulting ketos- sides. Sphingolipids are then transported saccharide moiety, several glycosphingo- phinganine is reduced to sphinganine pri- and inserted in various membranes. lipid lineages (ganglio-, globo- etc.) have or to N-acylation by ceramide synthases . been defined. ›Cerebroside‹ usually refers Distinct fatty acids, including 2-hydroxy- Degradation to the major myelin lipid galactosylcer- lated long chain fatty acids and ω-hydrox- . Fig. 38.2. amide; ›sulfatide‹ to its sulfated deriva- ylated ultra-long chain fatty acids, can be After transport by the endolysosomal tive. Lysosphingolipids (e.g. psychosine ) incorporated. Then, dihydroceramide is pathway to the lysosome, sphingolipid lack the fatty acid of ceramide. The main desaturated to produce ceramide. The degradation proceeds by stepwise hydrol- sphingolipids are depicted in . Fig. 38.1 sphingosine that is released by the action ysis by specific acid sphingohydrolases, and . Fig. 38.2. Sphingolipids are synthe- of ceramidases on the ceramide derived some of which may need co-factors called sised and degraded in different cellular from the degradation of complex sphin- sphingolipid activator proteins (also compartments. A further aspect of sphin- golipids can also be N-acylated by lysosomal) for their in vivo action. golipid homeostasis not discussed here is ceramide synthases. Subsequent steps of the recycling or salvage pathway. sphingolipid synthesis (except galactosyl- ceramide) occur in the Golgi apparatus, Biosynthesis where ceramide is processed to sphingo- . Fig. 38.1. myelin or to glucosylceramide ; stepwise The de novo synthesis of ceramide occurs addition of further monosaccharides, in the endoplasmic reticulum and starts catalysed by specific glycosyltransferases , Sphingolipidoses are a subgroup of lysosomal storage disorders cholesterol and sphingolipids. This chapter also describes in which sphingolipids accumulate in one or several organs as neuronal ceroid lipofuscinoses, now recognised as another the result of a primary deficiency in enzymes or activator pro- subgroup of lysosomal storage diseases. Additionally, inherited teins. Niemann-Pick type C disease is currently considered as a defects of sphingolipid biosynthesis are presented (7 Sphingo- lipid trafficking disorder, resulting in lysosomal accumulation of lipid Structure and Metabolism). 38.1 Disorders of Sphingolipid Synthesis although biochemical testing in plasma is possible for detec- tion of HSAN1. There is currently no effective specific therapy Most of the genes encoding the enzymes, transporters and for this type of IEMs. Most of these conditions remain activators operating in the sphingolipid synthesis pathway extremely rare. Their clinical spectrum is broadening with have been characterised, and an increasing number of mono- description of new cases and the field is likely to quickly evolve genic defects affecting some steps of the biosynthesis of sphin- in the near future. For these reasons, and since comprehensive golipids have been delineated in recent years (. Table 38.1). A reviews on the subject with exhaustive referencing have been majority of disorders were first described as a component of a published very recently [1][2], only a brief outline of each dis- genetically heterogeneous clinical syndrome -e.g., hereditary order will be given in this chapter. sensory and autonomic neuropathies (HSAN), autosomal re- cessive hereditary spastic paraplegias… – before the function of the protein encoded by the mutated gene was recognised. 38.1.1 Serine Palmitoyltransferase Mechanisms underlying the pathophysiology of most sphin- (Subunit 1 or 2) Deficiency and HSAN1 golipid synthesis disorders are still enigmatic. With the excep- tion of HSAN1, the reported mutations result in a loss of func- A defect in the very first step of sphingolipid biosynthesis is tion of the corresponding enzyme. Alterations in the sphingo- the major cause underlying the dominant hereditary sensory lipid profile of the diseased tissues have not been described in and autonomic neuropathy (HSAN1) . Other (unrelated) all conditions. In general, it is still unknown whether tissue genes that have been linked to HSAN1 are ATL1, RAB7A and dysfunction and symptoms are due to the lack (or insufficient DNMT1 [1]. This peripheral neuropathy is characterised by a production) of one or more sphingolipid species, and/or accu- late onset (between the 2nd and 4th decade), a slow disease mulation of a precursor molecule or a potentially toxic metab- progression, and primarily sensory deficits (loss of pain and olite. temperature sensation spreading from the distal limbs). Pain- Regarding genetic transmission, with the exception of less ulcerations in the lower limbs are quite frequent, as well as HSAN1 due to a defect in serine palmitoyltransferase 1 or 2, spontaneous lancinating pain attacks. Hypohidrosis is also and possibly the defect in ceramide synthase 2, enzymatic de- seen. Some patients exhibit a more severe phenotype, starting ficiencies of sphingolipid synthesis are inherited as autosomal in early childhood, with motor involvement, global hypotro- recessive traits. So far, their diagnosis relies on DNA analysis phy, and developmental retardation [1]. 554 Chapter 38 · Disor ders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses . Table 38.1 Sphingolipid biosynthesis disorders Enzyme Gene Metabolic disturbance Main clinical features Disorders with primarily nervous system involvement Serine palmitoyltrans- SPTLC1 or Accumulation of 1-deoxysphingolipids [HSAN1] - Peripheral sensory neuropathy, ferase, subunit 1 or 2 SPTLC2 (in plasma) distal sensory loss, ulcerative mutilations Ceramide synthase 1 CERS1 Possibly decreased C18-ceramide levels Progressive myoclonic epilepsy and (in cultured cells) cognitive decline Ceramide synthase 2 CERS2 Possibly decreased very-long chain Progressive myoclonic epilepsy ceramide levels (in cultured cells) Fatty
Load more

Recommended publications
  • Combination of Photodynamic Therapy with Fenretinide and C6
    Wayne State University Wayne State University Theses 1-1-2015 Combination Of Photodynamic Therapy With Fenretinide And C6-Pyridinium Ceramide Enhances Killing Of Scc17b Human Head And Neck Squamous Cell Carcinoma Cells Via The eD Novo Sphingolipid Biosynthesis And Mitochondrial Apoptosis Nithin Bhargava Boppana Wayne State University, Follow this and additional works at: https://digitalcommons.wayne.edu/oa_theses Part of the Medicinal Chemistry and Pharmaceutics Commons Recommended Citation Boppana, Nithin Bhargava, "Combination Of Photodynamic Therapy With Fenretinide And C6-Pyridinium Ceramide Enhances Killing Of Scc17b Human Head And Neck Squamous Cell Carcinoma Cells Via The eD Novo Sphingolipid Biosynthesis And Mitochondrial Apoptosis" (2015). Wayne State University Theses. 431. https://digitalcommons.wayne.edu/oa_theses/431 This Open Access Thesis is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Theses by an authorized administrator of DigitalCommons@WayneState. COMBINATION OF PHOTODYNAMIC THERAPY WITH FENRETINIDE AND C6-PYRIDINIUM CERAMIDE ENHANCES KILLING OF SCC17B HUMAN HEAD AND NECK SQUAMOUS CELL CARCINOMA CELLS VIA THE DE NOVO SPHINGOLIPID BIOSYNTHESIS AND MITOCHONDRIAL APOPTOSIS by NITHIN BHARGAVA BOPPANA THESIS Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE 2015 MAJOR: PHARMACEUTICAL SCIENCES Approved By: ________________________________ Advisor Date © COPYRIGHT BY NITHIN BHARGAVA BOPPANA 2015 All Rights Reserved DEDICATION Dedicated to my mom Rekha Vasireddy for always believing in me and helping me in becoming the person who I am today. ii ACKNOWLEDGEMENTS I am grateful to my advisor, Dr. Duska Separovic for her invaluable mentorship throughout the project.
    [Show full text]
  • The CLN5 Disease
    Mia-Lisa Schmiedt Mia-Lisa Schmiedt Mia-Lisa Schmiedt The CLN5 disease − RESEARCH protein maturation, RESEARCH The CLN5 disease − protein maturation, trafficking and pathology trafficking and pathology The CLN5 disease −protein maturation, trafficking and pathology and trafficking maturation, The CLN5 disease −protein Neuronal ceroid lipofuscinoses (NCLs) are a group of hereditary neurode- generative disorders primarily affecting children. Characteristics for NCLs are accumulation of autofluorescent storage material, neuronal degenera- tion, motor disturbances, progressive loss of vision and premature death. One member of the NCL family is the CLN5 disease, a late infantile variant phenotype form, caused by mutations in the CLN5 gene. CLN5 encodes a lysosomal protein of unidentified function. This thesis work contributes to the basic understanding of the molecular and cell biological mechanisms underlying CLN5 disease. Real-time PCR studies indicated that Cln5 gene expression increases gradually in the mouse brain with age and its expres- sion is highest in microglia. This thesis project further presents that the CLN5 protein is cleaved in the ER, trimmed and finally traffics to lysosomes. CLN5 constructs carrying different disease causing mutations revealed that trafficking is disturbed with varying severity depending on the particular mutation. Also, this work provides novel aspects about the early events in the pathogenesis of CLN5 disease, late infantile variant, links Cln5 to lipid metabolism and strengthens the recently reported
    [Show full text]
  • Soonerstart Automatic Qualifying Syndromes and Conditions 001
    SoonerStart Automatic Qualifying Syndromes and Conditions 001 Abetalipoproteinemia 272.5 002 Acanthocytosis (see Abetalipoproteinemia) 272.5 003 Accutane, Fetal Effects of (see Fetal Retinoid Syndrome) 760.79 004 Acidemia, 2-Oxoglutaric 276.2 005 Acidemia, Glutaric I 277.8 006 Acidemia, Isovaleric 277.8 007 Acidemia, Methylmalonic 277.8 008 Acidemia, Propionic 277.8 009 Aciduria, 3-Methylglutaconic Type II 277.8 010 Aciduria, Argininosuccinic 270.6 011 Acoustic-Cervico-Oculo Syndrome (see Cervico-Oculo-Acoustic Syndrome) 759.89 012 Acrocephalopolysyndactyly Type II 759.89 013 Acrocephalosyndactyly Type I 755.55 014 Acrodysostosis 759.89 015 Acrofacial Dysostosis, Nager Type 756.0 016 Adams-Oliver Syndrome (see Limb and Scalp Defects, Adams-Oliver Type) 759.89 017 Adrenoleukodystrophy, Neonatal (see Cerebro-Hepato-Renal Syndrome) 759.89 018 Aglossia Congenita (see Hypoglossia-Hypodactylia) 759.89 019 Albinism, Ocular (includes Autosomal Recessive Type) 759.89 020 Albinism, Oculocutaneous, Brown Type (Type IV) 759.89 021 Albinism, Oculocutaneous, Tyrosinase Negative (Type IA) 759.89 022 Albinism, Oculocutaneous, Tyrosinase Positive (Type II) 759.89 023 Albinism, Oculocutaneous, Yellow Mutant (Type IB) 759.89 024 Albinism-Black Locks-Deafness 759.89 025 Albright Hereditary Osteodystrophy (see Parathyroid Hormone Resistance) 759.89 026 Alexander Disease 759.89 027 Alopecia - Mental Retardation 759.89 028 Alpers Disease 759.89 029 Alpha 1,4 - Glucosidase Deficiency (see Glycogenosis, Type IIA) 271.0 030 Alpha-L-Fucosidase Deficiency (see Fucosidosis)
    [Show full text]
  • Inherited Monogenic Defects of Ceramide Metabolism Molecular
    Clinica Chimica Acta 495 (2019) 457–466 Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/cca Review Inherited monogenic defects of ceramide metabolism: Molecular bases and diagnoses T ⁎⁎ Patricia Dubota,b, Frédérique Sabourdya,b, Jitka Rybovac,Jeffrey A. Medinc,d, , ⁎ Thierry Levadea,b, a Laboratoire de Biochimie Métabolique, Centre de Référence en Maladies Héréditaires du Métabolisme, Institut Fédératif de Biologie, CHU de Toulouse, Toulouse, France b INSERM UMR1037, CRCT (Cancer Research Center of Toulouse), Université Paul Sabatier, Toulouse, France c Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA d Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA ABSTRACT Ceramides are membrane lipids implicated in the regulation of numerous biological functions. Recent evidence suggests that specific subsets of molecular species of ceramide may play distinct physiological roles. The importance of this family of molecules in vertebrates is witnessed by the deleterious consequences of genetic alterations in ceramide metabolism. This brief review summarizes the clinical presentation of human disorders due to the deficiency of enzymes involved either in the biosynthesis or the degradation of ceramides. Information on the possible underlying pathophysiological mechanisms is also provided, based on knowledge gathered from animal models of these inherited rare conditions. When appropriate, tools for chemical and molecular diagnosis of these disorders and therapeutic options are also presented. 1. Introduction/foreword relationships that are relevant for unraveling the biological role of these genes and gene products in humans. Studies on ceramides and sphingolipid metabolism have attracted a lot of attention recently. This is largely related to the multiplicity of 2.
    [Show full text]
  • Implications in Parkinson's Disease
    Journal of Clinical Medicine Review Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease Silvia Paciotti 1,2 , Elisabetta Albi 3 , Lucilla Parnetti 1 and Tommaso Beccari 3,* 1 Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Sant’Andrea delle Fratte, 06132 Perugia, Italy; [email protected] (S.P.); [email protected] (L.P.) 2 Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Sant’Andrea delle Fratte, 06132 Perugia, Italy 3 Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti, 06123 Perugia, Italy; [email protected] * Correspondence: [email protected] Received: 29 January 2020; Accepted: 20 February 2020; Published: 21 February 2020 Abstract: Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson’s disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson’s disease. Keywords: ceramide metabolism; Parkinson’s disease; α-synuclein; GBA; GLA; HEX A-B; GALC; ASAH1; SMPD1; ARSA * Correspondence [email protected] 1.
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • Dystonia and Chorea in Acquired Systemic Disorders
    J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.436 on 1 October 1998. Downloaded from 436 J Neurol Neurosurg Psychiatry 1998;65:436–445 NEUROLOGY AND MEDICINE Dystonia and chorea in acquired systemic disorders Jina L Janavs, Michael J AminoV Dystonia and chorea are uncommon abnormal Associated neurotransmitter abnormalities in- movements which can be seen in a wide array clude deficient striatal GABA-ergic function of disorders. One quarter of dystonias and and striatal cholinergic interneuron activity, essentially all choreas are symptomatic or and dopaminergic hyperactivity in the nigros- secondary, the underlying cause being an iden- triatal pathway. Dystonia has been correlated tifiable neurodegenerative disorder, hereditary with lesions of the contralateral putamen, metabolic defect, or acquired systemic medical external globus pallidus, posterior and poste- disorder. Dystonia and chorea associated with rior lateral thalamus, red nucleus, or subtha- neurodegenerative or heritable metabolic dis- lamic nucleus, or a combination of these struc- orders have been reviewed frequently.1 Here we tures. The result is decreased activity in the review the underlying pathogenesis of chorea pathways from the medial pallidus to the and dystonia in acquired general medical ventral anterior and ventrolateral thalamus, disorders (table 1), and discuss diagnostic and and from the substantia nigra reticulata to the therapeutic approaches. The most common brainstem, culminating in cortical disinhibi- aetiologies are hypoxia-ischaemia and tion. Altered sensory input from the periphery 2–4 may also produce cortical motor overactivity medications. Infections and autoimmune 8 and metabolic disorders are less frequent and dystonia in some cases. To date, the causes. Not uncommonly, a given systemic dis- changes found in striatal neurotransmitter order may induce more than one type of dyski- concentrations in dystonia include an increase nesia by more than one mechanism.
    [Show full text]
  • Enhancing Skin Health: by Oral Administration of Natural Compounds and Minerals with Implications to the Dermal Microbiome
    Review Enhancing Skin Health: By Oral Administration of Natural Compounds and Minerals with Implications to the Dermal Microbiome David L. Vollmer 1, Virginia A. West 1 and Edwin D. Lephart 2,* 1 4Life Research, Scientific Research Division, Sandy, Utah 84070, USA; [email protected] (D.L.V.); [email protected] (V.A.W) 2 Department of Physiology, Developmental Biology and The Neuroscience Center, Brigham Young University, Provo, Utah 84602, USA * Correspondence: [email protected]; Tel.: +1-801-422-2006 Received: 23 August 2018; Accepted: 1 October 2018; Published: 7 October 2018 Abstract: The history of cosmetics goes back to early Egyptian times for hygiene and health benefits while the history of topical applications that provide a medicinal treatment to combat dermal aging is relatively new. For example, the term cosmeceutical was first coined by Albert Kligman in 1984 to describe topical products that afford both cosmetic and therapeutic benefits. However, beauty comes from the inside. Therefore, for some time scientists have considered how nutrition reflects healthy skin and the aging process. The more recent link between nutrition and skin aging began in earnest around the year 2000 with the demonstrated increase in peer-reviewed scientific journal reports on this topic that included biochemical and molecular mechanisms of action. Thus, the application of: (a) topical administration from outside into the skin and (b) inside by oral consumption of nutritionals to the outer skin layers is now common place and many journal reports exhibit significant improvement for both on a variety of dermal parameters. Therefore, this review covers, where applicable, the history, chemical structure, and sources such as biological and biomedical properties in the skin along with animal and clinical data on the oral applications of: (a) collagen, (b) ceramide, (c) β-carotene, (d) astaxanthin, (e) coenzyme Q10, (f) colostrum, (g) zinc, and (h) selenium in their mode of action or function in improving dermal health by various quantified endpoints.
    [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]
  • Palmitoyl-Protein Thioesterase 1 Deficiency in Drosophila Melanogaster Causes Accumulation
    Genetics: Published Articles Ahead of Print, published on February 1, 2006 as 10.1534/genetics.105.053306 Palmitoyl-protein thioesterase 1 deficiency in Drosophila melanogaster causes accumulation of abnormal storage material and reduced lifespan Anthony J. Hickey*,†,1, Heather L. Chotkowski*, Navjot Singh*, Jeffrey G. Ault*, Christopher A. Korey‡,2, Marcy E. MacDonald‡, and Robert L. Glaser*,†,3 * Wadsworth Center, New York State Department of Health, Albany, NY 12201-2002 † Department of Biomedical Sciences, State University of New York, Albany, NY 12201-0509 ‡ Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114 1 current address: Albany Medical College, Albany, NY 12208 2 current address: Department of Biology, College of Charleston, Charleston, SC 294243 3 corresponding author: Wadsworth Center, NYS Dept. Health, P. O. Box 22002, Albany, NY 12201-2002 E-mail: [email protected] 1 running title: Phenotypes of Ppt1-deficient Drosophila key words: Batten disease infantile neuronal ceroid lipofuscinosis palmitoyl-protein thioesterase CLN1 Drosophila corresponding author: Robert L. Glaser Wadsworth Center, NYS Dept. Health P. O. Box 22002 Albany, NY 12201-2002 E-mail: [email protected] phone: 518-473-4201 fax: 518-474-3181 2 ABSTRACT Human neuronal ceroid lipofuscinoses (NCLs) are a group of genetic neurodegenerative diseases characterized by progressive death of neurons in the central nervous system (CNS) and accumulation of abnormal lysosomal storage material. Infantile NCL (INCL), the most severe form of NCL, is caused by mutations in the Ppt1 gene, which encodes the lysosomal enzyme palmitoyl-protein thioesterase 1 (Ppt1). We generated mutations in the Ppt1 ortholog of Drosophila melanogaster in order to characterize phenotypes caused by Ppt1-deficiency in flies.
    [Show full text]
  • 743914V1.Full.Pdf
    bioRxiv preprint doi: https://doi.org/10.1101/743914; this version posted August 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Cross-talks of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis 2 and ER-associated degradation 3 4 Yicheng Wang1,2, Yusuke Maeda1, Yishi Liu3, Yoko Takada2, Akinori Ninomiya1, Tetsuya 5 Hirata1,2,4, Morihisa Fujita3, Yoshiko Murakami1,2, Taroh Kinoshita1,2,* 6 7 1Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 8 2WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, 9 Japan 10 3Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, 11 School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, China 12 4Current address: Center for Highly Advanced Integration of Nano and Life Sciences (G- 13 CHAIN), Gifu University, 1-1 Yanagido, Gifu-City, Gifu 501-1193, Japan 14 15 *Correspondence and requests for materials should be addressed to T.K. (email: 16 [email protected]) 17 18 19 Glycosylphosphatidylinositol (GPI)-anchored proteins and glycosphingolipids interact with 20 each other in the mammalian plasma membranes, forming dynamic microdomains. How their 21 interaction starts in the cells has been unclear. Here, based on a genome-wide CRISPR-Cas9 22 genetic screen for genes required for GPI side-chain modification by galactose in the Golgi 23 apparatus, we report that b1,3-galactosyltransferase 4 (B3GALT4), also called GM1 24 ganglioside synthase, additionally functions in transferring galactose to the N- 25 acetylgalactosamine side-chain of GPI.
    [Show full text]
  • Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency
    Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency By Fabian Yu A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Fabian PS Yu 2018 Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency Fabian Yu Doctor of Philosophy Institute of Medical Science University of Toronto 2018 Abstract Farber disease (FD) is a devastating Lysosomal Storage Disorder (LSD) caused by mutations in ASAH1, resulting in acid ceramidase (ACDase) deficiency. ACDase deficiency manifests along a broad spectrum but in its classical form patients die during early childhood. Due to the scarcity of cases FD has largely been understudied. To circumvent this, our lab previously generated a mouse model that recapitulates FD. In some case reports, patients have shown signs of visceral involvement, retinopathy and respiratory distress that may lead to death. Beyond superficial descriptions in case reports, there have been no in-depth studies performed to address these conditions. To improve the understanding of FD and gain insights for evaluating future therapies, we performed comprehensive studies on the ACDase deficient mouse. In the visual system, we reported presence of progressive uveitis. Further tests revealed cellular infiltration, lipid buildup and extensive retinal pathology. Mice developed retinal dysplasia, impaired retinal response and decreased visual acuity. Within the pulmonary system, lung function tests revealed a decrease in lung compliance. Mice developed chronic lung injury that was contributed by cellular recruitment, and vascular leakage. Additionally, we report impairment to lipid homeostasis in the lungs. ii To understand the liver involvement in FD, we characterized the pathology and performed transcriptome analysis to identify gene and pathway changes.
    [Show full text]