Catecholamine Research in the 21st Century. Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012 PDF
Preview Catecholamine Research in the 21st Century. Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012
Catecholamine Research in the 21st Century Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012 Catecholamine Research in the 21st Century Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012 Lee E. Eiden AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO AcademicPressisanimprintofElsevier Academic Press is an imprint ofElsevier 32 Jamestown Road, London NW17BY, UK 225 WymanStreet, Waltham, MA 02451, USA 525 B Street, Suite1800,San Diego, CA 92101-4495,USA Copyright r 2013 ElsevierInc. All rights reserved No partof thispublication may be reproduced, stored inaretrieval system or transmittedin any form orby any means electronic,mechanical, photocopying, recordingor otherwisewithoutthe priorwrittenpermission ofthe publisher Permissions may be sought directly fromElsevier’s Science &Technology Rights Department in Oxford, UK: phone (144)(0) 1865 843830; fax (144) (0) 1865 853333; email: [email protected]. Alternatively, visit the Science and TechnologyBooks website at www.elsevierdirect.com/rights for further information Notice No responsibilityis assumedby the publisherfor anyinjury and/or damage topersons orproperty as amatter ofproducts liability, negligence or otherwise,orfrom anyuse oroperation ofany methods, products, instructions orideascontained inthe materialherein. Because ofrapid advancesinthe medical sciences, inparticular, independentverificationof diagnoses and drugdosages should bemade British Library Cataloguing-in-Publication Data A catalogue record for this bookis available from the BritishLibrary Library ofCongress Cataloging-in-Publication Data A catalog record for this bookis available from the Library ofCongress ISBN:978-0-12-800044-1 ForinformationonallAcademicPresspublications visit ourwebsite at elsevierdirect.com Typeset by MPS Limited, Chennai, India www.adi-mps.com Printed andboundin the United States 14 15 16 17 18 10 9 8 7 6 5 4 3 2 1 Preface The Tenth International Catecholamine Symposium (XICS) was held at The Asilomar Conference Grounds in Pacific Grove CA, September 9-13, 2012. It was the first international symposium focusedon catecholaminesinthe 21st century,providingthe title for theproceedings ofthe sympo- sium found in this volume. David Goldstein, founding Chief of the Clinical Neurocardiology Section, NINDS and President of the 8th International Catecholamine Symposium, also held at Asilomar in 1996, provided the guiding inspiration for the XICS. Daniel O’Connor, Professor of Medicine and Pharmacology at the Institute for Genomic Medicine, University of California San Diego, and President of the Catecholamine Society was also President of the 10th International Catecholamine Symposium. David Sibley, Chief of the Molecular Neuropharmacology Section, NINDS, Bethesda, MD, Esther Sabban, Professor of Biochemisty and Molecular Biology, New York Medical College, and the editor of this volume constituted the XICS Executive Organizing Committee. Many others, most especially the participants who came from Austria, Canada, The Czech Republic, Denmark, France, Germany, Israel, Italy, Japan, Mexico, Norway, Russian, Taiwan, the United States and elsewhere, contributed importantly to the success of the XICS. The editor wishes to thank Dave Goldstein and Dan O’Connor especially for their devotion to the even- tual completion ofthe Symposium andtheseproceedings. Some of the broader topics most relevant to the current status of catecholamine research as a trans- lational field have been covered in greater depth, by thought leaders in catecholamine research who were in attendance at the XICS, in a companion volume of Advances in Pharmacology. These include mechanisms of catecholamine biochemistry, cell biology, systems biology, clinical diagno- sis, drug discovery and target discovery, and gene therapeutic treatment for catecholamine-related human disease. Contained herein are the comprehensive conference proceedings in the form of extendedgraphical abstracts, and some condensed abstracts, ofalmost all of the presentations at the meeting organized into the ten themes under which the symposium was convened. The themes are introduced as chapters each with a short introduction that attempts to identify the highlights and ’growth areas’ within each. It is hoped that the reader will find these proceedings useful as a hand- book for the current state of play of catecholamine research, until such time as the Proceedings of the 11th International Catecholamine Symposium succeeds them. Lee E. Eiden Section on Molecular Neuroscience Laboratory ofCellular andMolecular Regulation National Institutesof Health Bethesda, MD, USA xxi THEME A Catecholamine Biosynthesis and Storage Lee Eiden and David Goldstein The major features of catecholamine biosynthesis [Tyrosine (TH) (cid:1)> L-Dopa (AADC) (cid:1)> DA (DBH) (cid:1)> NE (PNMT)(cid:1)> Epi] and storage [cytoplasmic DA, NE, Epi (cid:1)> VMAT1,2(cid:1)> vesicular DA, NE, Epi] were worked out well before the end of the previous century. This chapter contains illustrativeexamplesofprogresssince,andthisismanifestinamorecompletemolecularunderstand- ingofthecellbiologythatallowsTHtocontrolCAbiosynthesis;concreteclinicalstepsfordetection and gene therapy for catecholamine deficiency diseases; and complete identification of the combina- tions of catecholamine biosynthetic enzymes and vesicular storage capacity that can be found throughout the brain and periphery, and distinctly in rodent and primate neuronal systems, from whicha‘post-classical’viewofcatecholaminechemicalneuroanatomyhasemerged. While TH retains pride of place as the rate limiting enzyme for catecholamine biosynthesis, new insights into the conversion of tyrosine to L-Dopa have been gained by fuller exploration of the role of GTP cyclohydrolase (GTPCH) in supplying the necessary co-factor, tetrahydrobiopterin, for this enzymaticconversion.GTPCHandTHconvergebiochemicallyontyrosinetoallowitsconversionto CatecholamineResearchinthe21stCentury. 1 ©2014ElsevierInc.Allrightsreserved. 2 THEME A Catecholamine Biosynthesis and Storage L-Dopa, and thus share in this rate-limiting step for catecholamine production. This provides funda- mental molecular insights and clinical opportunities. One of the latter is that GTPCH deficiency occursinhumans,causesdisease,andcanpotentiallybecorrected. Enzymes in a metabolic pathwayare non-rate-limitingwhentheir increasedoesnot increaseturnover in the pathway: any enzyme becomes rate-limiting when its decrease or mis-trafficking cause its abundance to be less than the previous ‘rate-limiting enzyme’ in the pathway. Deficiency of AADC causes motor impairment that can be corrected by expression of AADC via viral vector-mediated genedeliverydirectlytothebrain. Insights into how different types of catecholaminergic neurons develop in the brain have indexed progress in developmental biology as a field. A surprising new insight is that the brain during devel- opment may itself be an endocrine organ secreting catecholamines to the rest of the body. The pre- sumption of developmental neuroscientists that ‘TH-positive’ neurons are dopaminergic or noradrenergic has been shattered in the last decade: there are DOPAergic and trace aminergic neu- rons, as well as neuronal dyads that synthesize dopamine only via intercellular collaboration. The notion that the chemical neuroanatomy of the human nervous system can be fully comprehended by study of the rodent nervous system has likewise been rendered untenable, and translational neurosci- ence is far better for it. Finally, exciting new vistas have emerged from the use of genetically-based lesioning and complementation experiments that show that subdivisions of the major catecholamine nuclei of the brain, including the locus coeruleus and substantia nigra, have surprising heterogeneity ofprojectionswithspecificanddistinctfunctions. Is further progress mainly a matter of effectively executing therapeutic strategies, or do further questionsremain?Theydo.Itisstillunclearforexample howsupplyofAADCtocellsofthestria- tum corrects a deficiency that inheres primarily in neurons that project to the striatum. The view that imaging of VMAT2 with TBZ reflects the molar concentration of the protein in the brain has given way to an emerging understanding that endogenous catecholamine levels play a role in how much TBZ binds to VMAT2 in the brains of normals, addicts to methamphetamine or cocaine, and patients with progressive degenerative disorders. The near-complete success of virus-mediated correction of brain defects related to catecholamine biosynthesis, and pharmacological correction of genetic deficiencies in catecholamine storage (see for example Rilstone et al., N. Engl. J. Med. 368, 543, 2013) show that robust clinical gains have resulted from translation of pre-2000 informa- tion, tools, and advances in allied fields. This in turn predicts that gains in new knowledge reported in this first, as well as the following chapters of “Catecholamine Research in the 21st Century” will likelyparlay into further therapeutic gains inthe coming decade. Genetic Manipulation of Catecholamine Signaling in the Mouse 3 Genetic Manipulation of Catecholamine Signaling in the Mouse Richard Palmiter UniversityofWashingtonSchoolofMedicineSeattle,Washington,USA Gene targeting in mouse embryonic stem cells has been used to generate mice that are unable to synthesize each of the major catecholamines. The developmental and behavioral consequences of making mice that are unable to synthesize epinephrine, norepinephrine and dopamine will be dis- cussed. I will illustrate how restoring dopamine signaling to specific brain regions of an otherwise dopamine-deficient mouse can restore viability and the ability to engage in specific behaviors. I will also show how we manipulate the activity of dopamine-producing neurons to affect the behavior ofmice. AADC Deficiency 3 Genetic Manipulation of Catecholamine Signaling in the Mouse Richard Palmiter UniversityofWashingtonSchoolofMedicineSeattle,Washington,USA Gene targeting in mouse embryonic stem cells has been used to generate mice that are unable to synthesize each of the major catecholamines. The developmental and behavioral consequences of making mice that are unable to synthesize epinephrine, norepinephrine and dopamine will be dis- cussed. I will illustrate how restoring dopamine signaling to specific brain regions of an otherwise dopamine-deficient mouse can restore viability and the ability to engage in specific behaviors. I will also show how we manipulate the activity of dopamine-producing neurons to affect the behavior ofmice. AADC Deficiency: Occurring in Humans; Modeled in Rodents; Treated in Patients Wuh-Liang Hwu1,Ni-Chung Lee1,Yih-DarShieh1,Kai-YuanTzen2,Pin-WenChen1, Shin-ichiMuramatsu3, Hiroshi Ichinose4 and Yin-Hsiu Chien1 1DepartmentofMedicalGenetics,Pediatrics;2NuclearMedicine,NationalTaiwanUniversityHospital; 3DivisionofNeurology,DepartmentofMedicine,JichiMedicalUniversity,Japan;4DepartmentofLifeScience, GraduateSchoolofBioscienceandBiotechnology,TokyoInstituteofTechnology,Japan Aromatic L-amino Acid Decarboxylase (AADC) deficiency (MIM #608643) is an autosomal recessive inborn error of neurotransmitter metabolism which causes severe motor dysfunction, oculogyric crisis, autonomic dysfunction, and emotional liability in patients since infancy. AADC deficiency is more common in Taiwan than in other countries because of a foundermutation (IVS614A.T). We have established a knock-in (KI) mouse model (DdcIVS6/IVS6) for AADC deficiency. Some of the homozygous KI mice were born alive, but they exhibited severe failure to thrive, dyskinesia, and clasping. However, if they could survive their first few weeks of lives, they then caught up in growth and improved in motor function. Gene therapy at neonatal stage 4 THEME A Catecholamine Biosynthesis and Storage could eliminate the manifestations of the disease. An attempt to treat patients with AADC deficiency was initiated before the establishment of the mouse model. AAV2-AADC vectors were infusued into the bilaterally putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: one patient was able to stand 16 months after gene transfer, and the other three patients gained head controls or achieved supported sitting. Choreic dyskinesia was observed in all patients, but this resolved after several months. 6-[18F]fluorodopa positron emission tomography (PET) and cerebrospinal fluid analysis both showed evidences of the treatment effects. 4 THEME A Catecholamine Biosynthesis and Storage could eliminate the manifestations of the disease. An attempt to treat patients with AADC deficiency was initiated before the establishment of the mouse model. AAV2-AADC vectors were infusued into the bilaterally putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: one patient was able to stand 16 months after gene transfer, and the other three patients gained head controls or achieved supported sitting. Choreic dyskinesia was observed in all patients, but this resolved after several months. 6-[18F]fluorodopa positron emission tomography (PET) and cerebrospinal fluid analysis both showed evidences of the treatment effects. Tyrosine Hydrolylase and Dopamine Beta-Hydroxylase: Role of Common Genetic Variation in Adrenergic Responses to Stress and in Hypertension Daniel O’Connor UCSD,USA RATIONALE: Catecholamine biosynthesis is catalyzed by a pathway of reactions in series. We asked whether the substantial inter-individual variation in catecholaminergic responses was in part heritable, and referable to genetic variation at loci encoding such enzymes. We also explored implications of pathway genetic variation for catecholamine secretion, environmental stress responses, and disease. METHODS:Wephenotypedcatecholaminergicresponsesintwinpairs(MZandDZ)toestimate trait heritability (h2), and re-sequenced the tyrosine hydroxylase (TH) and dopamine beta- hydroxylase (DBH) loci in n580 individuals (i.e., 2n5160 chromosomes) each for systematic polymorphism discovery. We explored whether such variants predicted catecholamine secretion, BP responses to environmental stress, or hypertension in the population. Finally, we tested chro- maffincell-transfectedluciferasereporterplasmidsforconsequencesofpromotervariation. RESULTS: Both catecholamine secretion and environmental stress (BP response to cold) traits were substantially heritable as judged by twin pair variance components. Most of the variation at TH and DBH occurred as bi-allelic SNPs (single nucleotide polymorphisms). Variations within the open readingframe(ORF),i.e.,non-synonymous(aminoacidreplacement)changes,wereunusual.Bycon- trast,functional,trait-associatedvariationwaslocalizedtothepromoterregionsofbothTHandDBH.
Description:The list of books you might like
