DOCSLIB.ORG

Peroxisomes and Aging ⁎ Stanley R

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Peroxisomes and Aging ⁎ Stanley R View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1763 (2006) 1749–1754 www.elsevier.com/locate/bbamcr Review Peroxisomes and aging ⁎ Stanley R. Terlecky a, , Jay I. Koepke a, Paul A. Walton b a Department of Pharmacology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, Michigan 48201, USA b Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada N6A 5C1 Received 23 May 2006; received in revised form 14 August 2006; accepted 18 August 2006 Available online 23 August 2006 Abstract Peroxisomes are indispensable for proper functioning of human cells. They efficiently compartmentalize enzymes responsible for a number of metabolic processes, including the absolutely essential β-oxidation of specific fatty acid chains. These and other oxidative reactions produce hydrogen peroxide, which is, in most instances, immediately processed in situ to water and oxygen. The responsible peroxidase is the heme- containing tetrameric enzyme, catalase. What has emerged in recent years is that there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset—leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific xenobiotics. The overall goal of this review is to summarize the molecular events associated with the development and advancement of peroxisomal hypocatalasemia and to describe its effects on cells. In addition, results of recent efforts to increase levels of peroxisomal catalase and restore oxidative balance in cells will be discussed. © 2006 Elsevier B.V. All rights reserved. Keywords: Aging; Catalase; Peroxisome; Protein import; Reactive oxygen specie; Senescence 1. Introduction contribution the organelle makes to the course of cellular aging. It is these latter questions that are the focus of this review. How peroxisomes are formed has been a topic of great Human cellular aging is multifactorial (see [1–3] and refer- interest to many investigators for several years now. Proteins ences therein); telomeres shorten, proteins are aberrantly gly- involved in various aspects of membrane assembly, protein cated, DNA is damaged and inefficiently or improperly repaired, import, and organelle maintenance and inheritance have been epigenetic events occur, protein expression is altered and reac- identified and how these molecules function mechanistically tive oxygen species accumulate and damage cellular constitu- elucidated in many cases. Although important questions remain, ents. No one process dominates under all circumstances— it is clear that overall, peroxisome biogenesis is relatively well rather they appear to conspire in some, perhaps varying, understood. combination. An important open question is what initiates the There is also a rich understanding of peroxisome biochem- aging cascade. One possibility is reactive oxygen species; istry and function as well as of how the organelle is turned over molecules with the capacity to damage, inactivate, and even during the processes known collectively as “pexophagy.” destroy cellular DNA, proteins, and lipids including biological Furthermore, the molecular basis of many devastating perox- membranes. isomal diseases has been delineated. Of no less importance, but Falling under the heading of reactive oxygen species and far less studied, are the questions of how the peroxisome related compounds are singlet oxygen, superoxide anion, functions in cells and organisms of advancing age and what hydrogen peroxide, and the hydroxyl radical. These cellular reactive oxygen species are produced primarily by mitochondria ⁎ Corresponding author. Tel.: +1 313 577 3557; fax: +1 313 577 6739. and peroxisomes [4]. Although peroxisomes probably do not E-mail address: [email protected] (S.R. Terlecky). generate near the amount of reactive oxygen species that mito- 0167-4889/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2006.08.017 1750 S.R. Terlecky et al. / Biochimica et Biophysica Acta 1763 (2006) 1749–1754 chondria do [1,5], they may very well be making them earlier— As pointed out above, catalase levels are found to be reduced an important point to be considered further below. in peroxisomes of aged rat livers [6,7,14]. Coupled with early Peroxisome aging was initially investigated using a rat liver reports that catalase was a rather poor substrate of the peroxisomal model. These important studies documented, for the first time, protein import apparatus [15], a more detailed examination of age-related differences in peroxisomal enzyme activities and catalase's import properties as a function of age was prompted. overall organelle function (see detailed summary [6]). Important Perhaps not surprisingly, catalase's import capacity too declined follow-up work by Badr and colleagues confirmed the reduced significantly with age (Terlecky, S.R., Koepke, J.I., and Walton, P. activities of peroxisomal β-oxidation enzymes and catalase in A., unpublished results]. Catalase is a PTS1-containing enzyme aging rat liver, and suggested that with respect to the former, whose import is mediated by Pex5p [16]. However, its PTS1 is a diminished levels of the peroxisome proliferator-activated tetrapeptide, lysine–alanine–asparagine–leucine (KANL) [16], receptor alpha (PPARα)-binding partner, retinoid X receptor largely unrelated to the consensus motif described above. This alpha (RXRα), may be responsible [7]. sequence is an extremely weak PTS1, only poorly directing More recently, human fibroblasts have been employed to catalase or other reporter proteins to which it is appended, to the study the specific relationship of peroxisomes and cellular organelle [13,17]. Combined with its upstream amino acids (in aging. These somatic cells may be cultured to various catalase), its “PTS1 predictor” score is a paltry 1.5. A weak import population doubling levels (PDL), with advancing PDLs substrate even in early passage cells, catalase's import is severely being viewed as akin to aging. At a certain point, these cells compromised in middle and late passage cells. Thus it appears experience an irreversible cell cycle arrest and are termed that although aging acts on all PTS1 enzymes with respect to their “senescent”. Characteristic biochemical and morphological import capacities, it is catalase with its weak KANL signal that is changes accompany cells' entry into the end of their replicative the most dramatically affected. lifespan. Perhaps the best validation of the model system comes from recent studies performed in primates demonstrating the 3. Pex5p presence of senescent cells at high frequencies in aged tissue [8]. 3.1. Binding A final note regarding cellular senescence; it has been suggested and evidence obtained to support the idea that cells One straightforward explanation for the distinct import ca- enter replicative senescence to avoid transformation and pacities of SKL-containing enzymes as compared to catalase is becoming cancerous [9]. Interestingly, the very environment differential binding by Pex5p. Several experimental approaches that promotes senescence—that is, the presence of reactive were brought to bear on the issue including fluorescence oxygen species both within cells and in the surrounding stroma, anisotropy, ligand blots, solid-phase (ELISA-type) assays, two- also potentiates initiation and progression of cancerous hybrid analysis, and surface plasmon resonance, among others transformation. [12,13,18]. The results were clear and consistent—proteins containing an SKL PTS1 were far better recognized and bound 2. PTS1 protein import in aging by Pex5p than the KANL-containing catalase molecule. Importantly, appending an SKL sequence in lieu of KANL The overwhelming majority of peroxisomal enzymes, in- increased catalase's recognition by Pex5p to the level seen with cluding most oxidases which produce hydrogen peroxide, other SKL-containing enzymes [13]. Catalase-SKL was not only contain a carboxy-terminal tripeptide closely related or identical recognized more avidly by Pex5p, but its import into peroxi- to serine–lysine–leucine (SKL) [10]. Called peroxisomal somes was also enhanced (Terlecky, S.R., Koepke, J.I., and targeting signal 1 (PTS1), this sequence and residues just Walton, P.A., unpublished results). upstream determine the enzymes' capacities to be recognized by What happens to Pex5p with age? Preliminary results the import receptor, Pex5p [10–12]. Conventional wisdom in suggest its affinity for PTS1 sequences is reduced (Terlecky, the field is that the strength of Pex5p's binding to a given S.R., Koepke, J.I., and Walton, P.A., unpublished results). As substrate determines its import efficiency. “PTS1 predictor” (see will be discussed below, aging cells accumulate hydrogen http://mendel.imp.ac.at/mendeljsp/sat/pts1/PTS1predictor.jsp), peroxide and other reactive oxygen species. Perhaps Pex5p is a powerful tool for the in silico analysis of relative PTS1 oxidatively damaged in that environment. The observation that strength, indicates that human peroxisomal oxidases consis- hydrogen peroxide-treated Pex5p binds PTS1 less well supports tently score in the 10–15 range—a point
Load more

Recommended publications
  • Antenatal Diagnosis of Inborn Errors Ofmetabolism
    816 ArchivesofDiseaseinChildhood 1991;66: 816-822 CURRENT PRACTICE Arch Dis Child: first published as 10.1136/adc.66.7_Spec_No.816 on 1 July 1991. Downloaded from Antenatal diagnosis of inborn errors of metabolism M A Cleary, J E Wraith The introduction of experimental treatment for Sample requirement and techniques used in lysosomal storage disorders and the increasing prenatal diagnosis understanding of the molecular defects behind By far the majority of antenatal diagnoses are many inborn errors have overshadowed the fact performed on samples obtained by either that for many affected families the best that can amniocentesis or chorion villus biopsy. For be offered is a rapid, accurate prenatal diag- some disorders, however, the defect is not nostic service. Many conditions remain at best detectable in this material and more invasive only partially treatable and as a consequence the methods have been applied to obtain a diagnos- majority of parents seek antenatal diagnosis in tic sample. subsequent pregnancies, particularly for those disorders resulting in a poor prognosis in terms of either life expectancy or normal neurological FETAL LIVER BIOPSY development. Fetal liver biopsy has been performed to The majority of inborn errors result from a diagnose ornithine carbamoyl transferase defi- specific enzyme deficiency, but in some the ciency and primary hyperoxaluria type 1. primary defect is in a transport system or Glucose-6-phosphatase deficiency (glycogen enzyme cofactor. In some conditions the storage disease type I) could also be detected by biochemical defect is limited to specific tissues this method. The technique, however, is inva- only and this serves to restrict the material avail- sive and can be performed by only a few highly able for antenatal diagnosis for these disorders.
    [Show full text]
  • Thesis Final
    PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis Author Maxwell, Megan Amanda Published 2004 Thesis Type Thesis (PhD Doctorate) School School of Biomolecular and Biomedical Sciences DOI https://doi.org/10.25904/1912/1930 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/366184 Griffith Research Online https://research-repository.griffith.edu.au PEX1 MUTATIONS IN AUSTRALASIAN PATIENTS WITH DISORDERS OF PEROXISOME BIOGENESIS Megan Amanda Maxwell, BSc, MSc(Hons) School of Biomolecular and Biomedical Science, Faculty of Science, Griffith University Submitted in fulfilment of the requirements of the degree of Doctor of Philosophy July, 2003 ABSTRACT The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the β-oxidation of very long chain fatty acids, the breakdown of peroxide and the α-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function.
    [Show full text]
  • Role of Catalase in Oxidative Stress-And Age-Associated
    Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 9613090, 19 pages https://doi.org/10.1155/2019/9613090 Review Article Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases Ankita Nandi,1 Liang-Jun Yan ,2 Chandan Kumar Jana,3 and Nilanjana Das 1 1Department of Biotechnology, Visva-Bharati University, Santiniketan, West Bengal 731235, India 2Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA 3Department of Chemistry, Purash-Kanpur Haridas Nandi Mahavidyalaya, P.O. Kanpur, Howrah, West Bengal 711410, India Correspondence should be addressed to Nilanjana Das; [email protected] Received 25 March 2019; Revised 18 June 2019; Accepted 14 August 2019; Published 11 November 2019 Academic Editor: Cinzia Signorini Copyright © 2019 Ankita Nandi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Reactive species produced in the cell during normal cellular metabolism can chemically react with cellular biomolecules such as nucleic acids, proteins, and lipids, thereby causing their oxidative modifications leading to alterations in their compositions and potential damage to their cellular activities. Fortunately, cells have evolved several antioxidant defense mechanisms (as metabolites, vitamins, and enzymes) to neutralize or mitigate the harmful effect of reactive species and/or their byproducts. Any perturbation in the balance in the level of antioxidants and the reactive species results in a physiological condition called “oxidative stress.” A catalase is one of the crucial antioxidant enzymes that mitigates oxidative stress to a considerable extent by destroying cellular hydrogen peroxide to produce water and oxygen.
    [Show full text]
  • Catalase ECAT005.Pdf
    BioAssay Systems Catalase ECAT005.pdf EnzyChrom TM Catalase Assay Kit (ECAT-100) Quantitative Colorimetric/Fluorimetric Catalase Determination DESCRIPTION CATALASE (EC 1.11.1.6), is an ubiquitous antioxidant enzyme that 95 µL Assay Buffer. Note: diluted H 2O2 is not stable. Prepare fresh catalyzes the decomposition of hydrogen peroxide (H2O2) to water and dilutions for each experiment. oxygen. Add 90 µL of the 50 µM Substrate to these wells to initiate the catalase catalase reaction. Tap plate quick to mix. Incubate 30 min at room temperature. During the incubation time, proceed with Steps 3 and 4 below. 2 H 2O2 O2 + 2 H 2O By preventing excessive H 2O2 build up, catalase allows important cellular 3. H2O2 Standard Curve . Mix 40µL of the 4.8 mM H2O2 with 440 µL processes which produce H 2O2 as a byproduct to occur safely. dH2O to yield 400 µM H2O2. Prepare standards as shown in the Table Deficiency in catalase activity has been associated with grey hair and below. Transfer 10 µL standards into separate wells of the 96-well peroxisomal disorder acatalasia. Simple, direct and high-throughput plate. Add 90 µL Assay Buffer to the standards. assays for catalase activity find wide applications. BioAssay Systems' improved assay directly measures catalase degradation of H 2O2 using a No 400 µM H2O2 + H 2O Vol ( µL) H2O2 ( µM) redox dye. The change in color intensity at 570nm or fluorescence 1 100 µL + 0 µL 100 400 intensity ( λem/ex = 585/530nm) is directly proportional to the catalase 2 60 µL + 40 µL 100 240 activity in the sample.
    [Show full text]
  • Lessons Learned
    Prevention and Reversal of Chronic Disease Copyright © 2019 RN Kostoff PREVENTION AND REVERSAL OF CHRONIC DISEASE: LESSONS LEARNED By Ronald N. Kostoff, Ph.D., School of Public Policy, Georgia Institute of Technology 13500 Tallyrand Way, Gainesville, VA, 20155 [email protected] KEYWORDS Chronic disease prevention; chronic disease reversal; chronic kidney disease; Alzheimer’s Disease; peripheral neuropathy; peripheral arterial disease; contributing factors; treatments; biomarkers; literature-based discovery; text mining ABSTRACT For a decade, our research group has been developing protocols to prevent and reverse chronic diseases. The present monograph outlines the lessons we have learned from both conducting the studies and identifying common patterns in the results. The main product of our studies is a five-step treatment protocol to reverse any chronic disease, based on the following systemic medical principle: at the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective. Implementation of the five-step treatment protocol is as follows: FIVE-STEP TREATMENT PROTOCOL TO REVERSE ANY CHRONIC DISEASE Step 1: Obtain a detailed medical and habit/exposure history from the patient. Step 2: Administer written and clinical performance and behavioral tests to assess the severity of symptoms and performance measures. Step 3: Administer laboratory tests (blood, urine, imaging, etc) Step 4: Eliminate ongoing contributing factors to the chronic disease Step 5: Implement treatments for the chronic disease This individually-tailored chronic disease treatment protocol can be implemented with the data available in the biomedical literature now. It is general and applicable to any chronic disease that has an associated substantial research literature (with the possible exceptions of individuals with strong genetic predispositions to the disease in question or who have suffered irreversible damage from the disease).
    [Show full text]
  • MASARYKOVA UNIVERZITA Lékařská Fakulta
    MASARYKOVA UNIVERZITA Léka řská fakulta Biologický ústav Sanatorium REPROMEDA Dizerta ční práce - přílohy Preimplanta ční genetická diagnostika chromozomálních abnormit a screening aneuploidií časných embryí v terapii sterilních a infertilních pár ů metodou fertilizace in vitro Vědní obor: Léka řská biologie 5103V023 Brno, 2009 MUDr. Kate řina Veselá SEZNAM P ŘÍLOH Příloha 1 Autosomální dominantní Mendelovsky d ědi čné choroby (4 strany) Příloha 2 Autosomální recesívní Mendelovsky d ědi čné choroby (8 stran) Příloha 3 X - vázané Mendelovsky d ědi čné choroby (2 strany) Sperm and embryo analysis in a carrier of supernumerary inv Příloha 4 (21 stran) dup(15) marker chromosome Hybridization of the 18 alpha–satellite probe to chromosome 1 Příloha 5 (4 strany) revealed in PGD Příloha 6 What next for preimplantation genetic screening? (3 strany) ESHRE PGD Consortium data collection VI: cycles from January Příloha 7 (4 strany) to December 2003 with pregnancy follow-up to October 2004 ESHRE PGD Consortium data collection V: Cycles from January Příloha 8 (19 stran) to December 2002 with pregnancy follow-up to October 2003 Příloha 9 Central data collection on PGD and screening (1 strana) Příloha 1 Autosomální dominantní Mendelovsky dědičné choroby (odkazuje na www.diseasesdatabase.com) 4-hydroxyphenylpyruvate hydroxylase deficiency Blue color blindness Acatalasia Blue rubber bleb nevus syndrome Achondroplasia Boomerang dysplasia Acro-dermato-ungual-lacrimal-tooth syndrome Branchio-oculo-facial syndrome Acrodysostosis syndrome Brugada syndrome Acrokerato-elastoidosis
    [Show full text]
  • Peroxisomal Disorders in Neurology
    Journal of the Neurological Sciences, 1988, 88:1-39 I Elsevier JNS 03095 Review article Peroxisomal disorders in neurology R. J. A. Wanders 1, H. S.A. Heymans 1'*, R. B. H. Schutgens l, P.G. Barth 2, H. van den Bosch 3 and J.M. Tager 4 Depts. of IPediatrics and 2Neurology, University Hospital Amsterdam, Amsterdam (The Netherlands), 3Laboratory of Biochemistry, State University Utrecht, Utrecht (The Netherlands), and 4Laboratory of Biochemistry, University of Amsterdam, Amsterdam (The Netherlands) (Received 18 August, 1988) (Accepted 29 August, 1988) SUMMARY Although peroxisomes were initially believed to play only a minor role in mam- malian metabolism, it is now clear that they catalyse essential reactions in a number of different metabolic pathways and thus play an indispensable role in intermediary metabolism. The metabolic pathways in which peroxisomes are involved include the biosynthesis of ether phospholipids and bile acids, the oxidation of very long chain fatty acids, prostaglandins and unsaturated long chain fatty acids and the catabolism of phytanate and (in man) pipecolate and glyoxylate. The importance of peroxisomes in cellular metabolism is stressed by the existence of a group of inherited diseases, the peroxisomal disorders, caused by an impairment in one or more peroxisomal functions. In the last decade our knowledge about per- oxisomes and peroxisomal disorders has progressed enormously and has been the subject of several reviews. New developments include the identification of several additional peroxisomal disorders, the discovery of the primary defect in several of these peroxisomal disorders, the recognition of novel peroxisomal functions and the applica- tion of complementation analysis to obtain information on the genetic relationship between the different peroxisomal disorders.
    [Show full text]
  • B Disorders of Autonomic Nervous System
    Application of the International Classification of Diseases to Neurology \ Second Edition World Health Organization Geneva 1997 First edition 1987 Second edition 1997 Application of the international classification of diseases to neurology: ICD-NA- 2nd ed. 1. Neurology - classification 2. Nervous system diseases - classification I. Title: ICD-NA ISBN 92 4 154502 X (NLM Classification: WL 15) The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. ©World Health Organization 1997 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of
    [Show full text]
  • Impaired Oxidation of Very Long Chain Fatty Acids in White Blood Cells, Cultured Skin Fibroblasts, and Amniocytes
    286 SINGH ET AL. 003 1-3998/84/1803-0286$02.00/0 PEDIATRIC RESEARCH Vol. 18, No. 3, 1984 Copyright O 1984 International Pediatric Research Foundation, Inc. Prinfed in U.S. A. Adrenoleukodystrophy: Impaired Oxidation of Very Long Chain Fatty Acids in White Blood Cells, Cultured Skin Fibroblasts, and Amniocytes INDERJIT SINGH,'41' ANN E. MOSER, HUGO W. MOSER, AND YASUO KISHIMOTO John F. Kennedy Institute, and the Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA Summary ALD is a genetically-determined, progressive disorder which affects mainly the adrenal cortex and the white matter of the We compared the formation of I4CO2from [I-I4C]fattyacids in nervous system (32). It is associated with the accumulation of homogenates of cultured skin fibroblasts and white blood cells saturated very long chain fatty acids (mainly C26:0, C25:0, and from 25 patients with adrenoleukodystrophy (ALD) and from 24 C24:O) in the cholesterol esters and gangliosides in these tissues controls. The ALD group included 16 boys with childhood ALD, (1 1, 17, 30). Accumulation of these same fatty acids has also five men with adrenomyeloneuropathy (AMN), and two boys and been reported in sphingomyelin and other lipid moieties of two girls with neonatal ALD. The substrates were unbranched plasma (23) and red blood cells (38) and in cultured skin fibro- saturated fatty acids ranging in chain length from 16-26 carbons. blasts (22), cultured muscle cells (I), and cultured amniocytes From C24:0, the radioactive C02production by homogenates of (24). ALD fibroblasts and white blood cells was 17% and 37% of Several types of ALD have been described.
    [Show full text]
  • President and Founder of the Portuguese Association for CDG and Other Rare Metabolic Diseases (APCDG-DMR)
    Vanessa Ferreira, PhD President and Founder of the Portuguese Association for CDG and other Rare Metabolic Diseases (APCDG-DMR) Member of the Spanish Association for CDG (AESCDG) EUROGLYCANET CDG representative at European Platform for Rare Disease Registries (Epirare) DISCLAIMER The views and opinions expressed in the following PowerPoint slides are those of the individual presenter. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws. Used by permission. All rights reserved. OUTLINE • INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority • THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG) • ACTIVITIES DONE BY APCDG-DMR o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research WHAT IS A RARE DISEASE? A rare disease in Europe is a disease affecting less than 1 in 2,000 citizens In the United States, a rare disease is any disease or condition that affects 1 in 1,500 people 29 million people affected in the EU 3 million people Spain 3 millions people in France (1 in 20) 600 000-800 000 people in Portugal 3.5 million people in the UK 1 million people in the Netherlands 25 million people USA APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 4 6,000 and 8,000 distinct rare diseases! 49 XXXXY 5p, Síndrome Acidemia Metilmalónica Homocistinuria, Tipo cbl C
    [Show full text]
  • Peroxisomes and Central Nervous System Dysgenesis and Dysfunction
    Developmental Neurobiulogy, edited by Philippe Evrard and Alexandra Minkowski. Nestle Nutrition Workshop Series, Vol. 12. Nestec Ltd.. Vevey/Raven Press, Ltd., New York © 1989. Peroxisomes and Central Nervous System Dysgenesis and Dysfunction Sidney L. Goldfischer Department of Pathology, Albert Einstein College of Medicine, The Bronx, New York 10461 Peroxisomes play a key role in a number of genetic diseases. These include disor- ders in which the activity of a peroxisomal enzyme is deficient and an extraordinary group of diseases in which the formation of the organelle itself is defective (1-3) (Table 1). DISORDERS OF PEROXISOMAL BIOGENESIS Zellweger's cerebrohepatorenal syndrome (CHRS) is the first disease in which defective formation of peroxisomes was described (4,5). Infants affected with this rare autosomal recessive disorder usually die within one year. Clinical features of the syndrome include a typical facial appearance, with hypertelorism, a high fore- head, and pursed lips; minor skeletal abnormalities; renal cortical cysts; and severe hepatic fibrosis. Iron storage is frequently seen in the early stage of the disease. The most prominent findings are in the central nervous system and include profound hy- potonia. Cerebral abnormalities include polymicrogyria, pachygyria, olivary dys- plasia, and defective neuronal migration. Gliosis and accumulations of lipid in glia are associated with myelin breakdown, and the disease has been described as a suda- nophilic leukodystrophy (6-9). Hepatocellular peroxisomes have not been detected in children with this disease. This remarkable finding has been confirmed by many laboratories (10-13). It is par- ticularly surprising in view of the fact that there are approximately 1,000 peroxi- somes in a normal human hepatocyte (14).
    [Show full text]
  • Nuove Politiche Per L'innovazione Nel Settore Delle Scienze Della Vita
    Laura Magazzini Fabio Pammolli Massimo Riccaboni WP CERM 03-2009 NUOVE POLITICHE PER L'INNOVAZIONE NEL SETTORE DELLE SCIENZE DELLA VITA ISBN 978-88-3289-038-9 INDICE EXECUTIVE SUMMARY .................................................................................. 2 1. Risorse e innovazione: fallimenti di mercato e logiche di intervento pubblico........... 2 2. Da raro a generale: nuovi modelli di sostegno mission-oriented alla ricerca e sviluppo nelle scienze della vita............................................................................... 31 2.1. Incentivi pubblici per la ricerca sulle malattie rare: il panorama internazionale.....37 Stati Uniti...........................................................................................................................................................................................37 Giappone.............................................................................................................................................................................................44 Australia..............................................................................................................................................................................................46 Unione Europea.............................................................................................................................................................................46 2.2. Incentivi pubblici per la ricerca sulle malattie rare: il panorama europeo.....................58 Francia ..................................................................................................................................................................................................58
    [Show full text]