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Mass Spectrometry of Non-Protein Amino Acids: BMAA and Neurodegenerative Diseases

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Mass Spectrometry of Non-Protein Amino Acids: BMAA and Neurodegenerative Diseases Mass Spectrometry of Non-protein Amino Acids: BMAA and Neurodegenerative Diseases Liying Jiang Doctoral Thesis in Analytical Chemistry at Stockholm University, Sweden 2015 Mass Spectrometry of Non-protein Amino Acids: BMAA and Neurodegenerative Diseases Liying Jiang Doctoral Thesis in Analytical Chemistry Department of Environmental Science and Analytical Chemistry Stockholm University 2015 Academic dissertation for the Degree of Doctor of Philosophy in Analytical Chemistry at Stockholm University to be publicly defended at 10:00 am on Thursday 9th of April 2015 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, Sweden Doctoral thesis in Analytical Chemistry Department of Environmental Science and Analytical Chemistry (ACES) Stockholm University Stockholm, Sweden, 2015 © 2015 Liying Jiang ISBN 978-91-7649-028-0 Printed by Holmbergs, Malmö, Sweden, 2015 Distributor: Department of Environmental Science and Analytical Chemistry, Stockholm University To my parents, Qunfeng and Yitang 献给我的父母,群锋和忆唐 Abstract Neurodegenerative diseases have been shown to correlate positively with an ageing population. The most common neurodegenerative diseases are amyotrophic lateral sclerosis (ALS), Parkinson’s disease and Alzheimer’s disease. The cause of these diseases is believed to be the interaction between genetic and environmental factors, synergistically acting with ageing. BMAA (β-methylamino-L-alanine) is one kind of toxin present in our environment and might play an important role in the development of those diseases. BMAA was initially isolated from cycad seeds in Guam, where the incidence of ALS/Parkinsonism-dementia complex among the indigenous people was 50 – 100 times higher than the rest of the world in the 1950’s. BMAA can induce toxic effects on rodents and primates. Furthermore, it can potentiate neuronal injury on cell cultures at concentrations as low as 10 µM. BMAA was reported to be produced by cyanobacteria, and could bio-magnify through the food chain. In this thesis, work was initially focused on the improvement of an existing analytical method for BMAA identification and quantification using liquid chromatography coupled with tandem mass spectrometry. Subsequently, the refined method was applied to environmental samples for probing alternative BMAA producer(s) in nature and to seafood samples for estimation of human exposure to this toxin. In Paper I, a systematic screening of the isomers of BMAA in a database was performed and seven potential isomers were suggested. Three of them were detected or suspected in natural samples. In Paper II, a deuterated internal standard was synthesized and used for quantifying BMAA in cyanobacteria. In Paper III, Diatoms were discovered to be a BMAA producer in nature. In Paper IV, ten popular species of seafood sold in Swedish markets were screened for BMAA. Half of them were found to contain BMAA at a level of 0.01 – 0.90 µg/g wet weight. In Future perspectives, the remaining questions important in this field are raised. Abstrakt Neurogenerativa sjukdomar har visats korrelera positivt hos en åldrande population i Guam. De vanligaste neurogenerativa sjukdomarna är amyotrofisk lateral skleros (ALS), Parkinson’s och Alzheimer’s sjukdom. Orsaken till dessa sjukdomar tros ligga bakom interaktioner mellan genetiska och miljöfaktorer,som synergiskt agerar med åldrandet. BMAA (β-methylamino-L- alanine)är ett toxin som finns närvarande i våra miljöer och kan spela en viktig roll i utvecklandet av dessa sjukdomar. BMAA var ursprungligen isolerad från cycad frön i Guam, där förekomsten av ALS/Parkinsonism-demenskomplex bland de infödda invånarna låg på en nivå 50 - 100 gånger högre än vid resten av världen under 1950-talet. BMAA kan inducera toxiska effekter hos gnagare och primater. Dessutom, kan det förstärka skador i cell kulturer vid koncentrationer så låg som 10 µM. BMAA som ska produceras från cyanobakterier kan biomagnifieras via mat kedjor. I denna avhandling, var arbetet initialt fokuserad på förbättring av en existerande analytisk metod för BMAA identifiering och kvantifiering vid användning utav vätske kromatografi kopplad med en trippel quadropol masspektrometer. Därefter, appliceras den förbättrade metoden på miljöprover för screena alternativt BMAA producenter in natur och skaldjur för en uppskattning för en mänsklig exponering till detta toxin. I Artikel I, ett systematiskt screening av isomerer från BMAA i databasen utfördes och sju potentiella isomerer föreslogs. Tre av dessa detekterades eller misstänktes i naturliga prov. I Artikel II, en denaturerad intern standard syntetiserades och användes för kvantifiering utav BMAA i cyanobakterier. I Artikel III, kiselalger upptäcktes vara en BMAA producent i naturen. I Artikel IV, tio populära fisk och skaldjur som säljs i den svenska marknaden undersöktes med avseende för BMAA. Hälften av dem påvisades innehålla BMAA vid en nivå av 0.01 – 0.90 µg/g i våtvikt. För Framtida perspektiv, den kvarvarande viktiga frågan i detta område är belysta. List of Publications I. Jiang L., Aigret B., De Borggraeve W. M., Spacil Z. & Ilag L. L. (2012) Selective LC- MS/MS method for the identification of BMAA from its isomers in biological samples. Analytical and Bioanalytical Chemistry 403: 1719-1730 DOI: 10.1007/s00216-012-5966-y The author was responsible for the design of the study, all the experimental work except chemical synthesis, data evaluation and a major part of writing the Paper. II. Jiang L., Johnston E., Åberg K. M., Nilsson U. and Ilag L. L. (2013) Strategy for quantifying trace levels of BMAA in cyanobacteria by LC/MS/MS. Analytical and Bioanalytical Chemistry 405: 1283-1292 DOI: 10.1007/s00216-012-6550-1 The author was responsible for partially generating the idea, design of the study, all the experimental work except chemical synthesis, data evaluation and writing the Paper. III. Jiang L., Eriksson J., Lage S., Jonasson S., Shams S., Mehine M., Ilag L. L. and Rasmussen U. (2014) Diatoms: A Novel Source for the Neurotoxin BMAA in Aquatic Environments. PLoS ONE 9(1): e84578 DOI:10.1371/journal.pone.0084578 The author was responsible for partially developing the sample preparation method, LC- MS/MS analysis, data evaluation and a major part of writing the Paper. IV. Jiang L., Kiselova N., Rosén J. and Ilag L. L. (2014) Quantification of neurotoxin BMAA (β-N-methylamino-L-alanine) in seafood from Swedish markets. Scientific Reports 4: 6931 DOI: 10.1038/srep06931 The author was responsible for generating the idea, a part of design of the study, a part of the experimental work, data evaluation and writing the Paper. Permissions to reproduce the publications were kindly obtained from the publishers. Publications/Manuscripts not included in the thesis: V. Jiang L., Dziedzic P., Spacil Z., Zhao G. L., Nilsson L., Ilag L. L. and Cordova A. (2014) Abiotic synthesis of amino acids and self-crystallization under prebiotic conditions. Scientific Reports 4: 6769 DOI: 10.1038/srep06769 The author was responsible for a part of the experiments, data evaluation and a major part of writing the Paper. VI. Jiang L. and Ilag L. L. (2014) Detection of endogenous BMAA in dinoflagellate (Heterocapsa triquetra) hints at evolutionary conservation and environmental concern. PubRaw Science 1 (2): 1-8 The author was responsible for all the experiments, data evaluation and a part of writing the Paper. VII. Karlsson O., Jiang L., Andersson M., Ilag L. L. and Brittebo E. B. (2014) Protein association of the neurotoxin and non-protein amino acid BMAA (β-N-methylamino-L- alanine) in the liver and brain following neonatal administration in rats. Toxicology Letters 226.1: 1-5 DOI: 10.1016/j.toxlet.2014.01.027. The author was responsible for a part of the experiments, a part of data evaluation and a part of writing the Paper. VIII. Banack S. A., Metcalf J. S., Jiang L., Craighead D., Ilag L. L. and Cox P. A. (2012) Cyanobacteria produce N-(2-aminoethyl)glycine, a backbone for Peptide nucleic acids which may have been the first genetic molecules for life on Earth. PLoS One 7:e49043 DOI: 10.1371/journal.pone.0049043 The author was responsible for a part of the experiments and a part of data evaluation. IX. Xie X., Backman D., Lebedev T. A., Artaev B. V., Jiang L., Ilag L. L., and Zubarev A. R. (2015) Primordial soup was edible: abiotically produced Miller-Urey mixture supports bacterial growth. Nature Communications, submitted The author was responsible for a part of the experiments, a part of data evaluation and a part of writing the Paper. X. Karlsson O., Jiang L., Ersson L., Malmström T., Ilag L. L. and Brittebo B. E. Protein association/binding of the neurotoxin BMAA in neonatal rat tissues. (manuscript) The author was responsible for a part of the experiments, a part of data evaluation and a part of writing the Paper. Table of Contents 1. Introduction ............................................................................................................................................................. 13 1.1 BMAA and neurodegenerative diseases .......................................................................................................... 13 1.2 BMAA toxicity.................................................................................................................................................... 14 1.2.1 Toxicokinetics ....................................................................................................................................... 14 1.2.2 In vivo study .........................................................................................................................................
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