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Mass Spectrometry of Non-protein Amino Acids: BMAA and Neurodegenerative Diseases
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.ORCID iD: 0000-0002-9118-9907
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science and Analytical Chemistry, Stockholm University , 2015. , 43 p.
Keyword [en]
Neurodegenerative diseases, BMAA, Isomers, LC-MS/MS, Cyanobacteria, Diatoms, Seafood contamination
National Category
Analytical Chemistry
Research subject
Analytical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-114110ISBN: 978-91-7649-028-0 (print)OAI: oai:DiVA.org:su-114110DiVA: diva2:789762
Public defence
2015-04-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2015-03-18 Created: 2015-02-20 Last updated: 2015-03-20Bibliographically approved
List of papers
1. Selective LC-MS/MS method for the identification of BMAA from its isomers in biological samples
Open this publication in new window or tab >>Selective LC-MS/MS method for the identification of BMAA from its isomers in biological samples
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2012 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 403, no 6, 1719-1730 p.Article in journal (Refereed) Published
Abstract [en]

Algal blooms are well-known sources of acute toxic agents that can be lethal to aquatic organisms. However, one such toxin, beta--methylamino--alanine (BMAA) is also believed to cause amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. The detection and identification of BMAA in natural samples were challenging until the recent introduction of reliable methods. However, the issue of potential interference from unknown isomers of BMAA present in samples has not yet been thoroughly investigated. Based on a systematic database search, we generated a list of all theoretical BMAA structural isomers, which was subsequently narrowed down to seven possible interfering compounds for further consideration. The seven possible candidates satisfied the requirements of chemical stability and also shared important structural domains with BMAA. Two of the candidates, 2,4-diaminobutyric acid (DAB) and -(2-aminoethyl) glycine (AEG) have recently been studied in the context of BMAA. A further isomer, beta-amino--methyl-alanine (BAMA), has to be considered because it can potentially yield the fragment ion, which is diagnostic for BMAA. Here, we report the synthesis and analysis of BAMA, together with AEG, DAB, and other isomers that are of interest in the separation and detection of BMAA in biological samples by using either high-performance liquid chromatography or ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. We detected for the first time BAMA in blue mussel and oyster samples. This work extends the previously developed liquid chromatography-tandem mass spectrometry platform Spacil et al. (Analyst 135:127, 2010) to allow BMAA isomers to be distinguished, improving the detection and identification of this important amino acid.

Keyword
ALS, Cyanobacteria, beta-amino-N-methylalanine (BAMA), AEG, DAB
National Category
Analytical Chemistry
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-79872 (URN)10.1007/s00216-012-5966-y (DOI)000304166500023 ()
Note

AuthorCount:5;

Available from: 2012-09-12 Created: 2012-09-11 Last updated: 2017-12-07Bibliographically approved
2. Strategy for quantifying trace levels of BMAA in cyanobacteria by LC/MS/MS
Open this publication in new window or tab >>Strategy for quantifying trace levels of BMAA in cyanobacteria by LC/MS/MS
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2013 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 4, 1283-1292 p.Article in journal (Refereed) Published
Abstract [en]

The cyanobacterial neurotoxin β-N-methylamino--alanine (BMAA) is an amino acid that is putatively associated with the pathology of amyotrophic lateral sclerosis/Parkinsonism –dementia complex (ALS-PDC) disease. It raises serious health risk concerns since cyanobacteria are ubiquitous thus making human exposure almost inevitable. The identification and quantification of BMAA in cyanobacteria is challenging because it is present only in trace amounts and occurs alongside structurally similar compounds such as BMAA isomers. This work describes an enhanced liquid chromatography/tandem mass spectrometry platform that can distinguish BMAA from its isomers β-amino-N-methyl-alanine, N-(2-oethyl) glycine (AEG), and 2,4-diaminobutyric acid, thus ensuring confident identification of BMAA. The method's sensitivity was improved fourfold by a post-column addition of acetonitrile. The instrument and method limits of detection were shown to be 4.2 fmol/injection (or 0.5 g/one column) and 0.1 μg/g dry weight of cyanobacteria, respectively. The quantification method uses synthesized deuterated BMAA as an internal standard and exhibits good linearity, accuracy, and precision. Matrix effects were also investigated, revealing an ion enhancement of around 18 %. A lab-cultured cyanobacterial sample (Leptolyngbya PCC73110) was analyzed and shown to contain about 0.73 μg/g dry weight BMAA. The isomer AEG, whose chromatographic properties closely resemble those of BMAA, was also detected. These results highlight the importance of distinguishing BMAA from its isomers for reliable identification as well as providing a sensitive and accurate quantification method for measuring trace levels of BMAA in cyanobacterial samples.

Keyword
ALS-PDC, Isomers, AEG, BMAA, Post-column addition, Matrix effect
National Category
Analytical Chemistry Organic Chemistry
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-83935 (URN)10.1007/s00216-012-6550-1 (DOI)000313735000014 ()
Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2017-12-06Bibliographically approved
3. Diatoms: A Novel Source for the Neurotoxin BMAA in Aquatic Environments
Open this publication in new window or tab >>Diatoms: A Novel Source for the Neurotoxin BMAA in Aquatic Environments
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, e84578Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a neurological disorder linked to environmental exposure to a non-protein amino acid, beta-N-methylamino-L-alanine (BMAA). The only organisms reported to be BMAA-producing, are cyanobacteria - prokaryotic organisms. In this study, we demonstrate that diatoms - eukaryotic organisms - also produce BMAA. Ultra-high-performance liquid chromatography coupled with tandem mass spectrometry revealed the occurrence of BMAA in six investigated axenic diatom cultures. BMAA was also detected in planktonic field samples collected on the Swedish west coast that display an overrepresentation of diatoms relative to cyanobacteria. Given the ubiquity of diatoms in aquatic environments and their central role as primary producers and the main food items of zooplankton, the use of filter and suspension feeders as livestock fodder dramatically increases the risk of human exposure to BMAA-contaminated food.

National Category
Biological Sciences Analytical Chemistry
Research subject
Analytical Chemistry; Plant Physiology
Identifiers
urn:nbn:se:su:diva-100864 (URN)10.1371/journal.pone.0084578 (DOI)000329460100066 ()
Note

AuthorCount:8;

Available from: 2014-02-19 Created: 2014-02-17 Last updated: 2017-12-06Bibliographically approved
4. Quantification of neurotoxin BMAA (beta-N-methylamino-L-alanine) in seafood from Swedish markets
Open this publication in new window or tab >>Quantification of neurotoxin BMAA (beta-N-methylamino-L-alanine) in seafood from Swedish markets
2014 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 4, 6931- p.Article in journal (Refereed) Published
Abstract [en]

The neurotoxin beta-N-methylamino-L-alanine (BMAA) produced naturally by cyanobacteria, diatoms and dinoflagellates can be transferred and accumulated up the food chain, and may be a risk factor for neurodegenerative diseases. This study provides the first systematic screening of BMAA exposure of a large population through the consumption of seafood sold in metropolitan markets. BMAA was distinguished from known isomers by liquid chromatography tandem mass spectrometry after acidic hydrolysis and derivatization. Using deuterium-labeled internal standard, BMAA was quantified as 0.01-0.90 mu g/g wet weight of tissues in blue mussel, oyster, shrimp, plaice, char and herring, but was undetectable (<0.01 mu g/g) in other samples (salmon, cod, perch and crayfish). Provided that the content of BMAA detected is relevant for intake calculations, the data presented may be used for a first estimation of BMAA exposure through seafood from Swedish markets, and to refine the design of future toxicological experiments and assessments.

National Category
Analytical Chemistry
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-110174 (URN)10.1038/srep06931 (DOI)000344315200003 ()
Note

AuthorCount:4;

Available from: 2015-02-09 Created: 2014-12-08 Last updated: 2017-12-04Bibliographically approved

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