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Detection, transfer and role of an environmentally spread neurotoxin (BMAA) with focus on cyanobacteria and the Baltic Sea region
Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.ORCID iD: 0000-0002-7453-1889
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

β-N-methylamino-L-alanine (BMAA) is one of the more recently discovered bioactive compounds produced by cyanobacteria. BMAA is a non-protein amino acid reported present in human brain tissues of patients deceased from a neurodegenerative disease, such as Alzheimer´s disease or amyotrophic lateral sclerosis (ALS). This observation in combination with its neurotoxic effects in eukaryotes (in vivo and in vitro) and its potential to incorporate into (human) proteins, causing protein aggregation, suggests BMAA as a possible causative environmental agent for neurodegenerative diseases. Due to the ubiquitous nature of cyanobacteria with a wide occurrence in both aquatic and terrestrial environments, BMAA could be globally spread. Hence, investigations of a possible coupling between BMAA and neurodegeneration are urgently needed as well as to identify sources of BMAA in Nature.

The aim of this thesis was to examine the potential occurrence of BMAA in bloom forming cyanobacteria of the Baltic Sea and its possible transfer to other organisms of this ecosystem. Of importance was also to reveal any likely routes for human BMAA exposure in the Baltic Sea region and to further investigate BMAA as a triggering agent for neurodegenerative diseases. Acknowledged difficulties of analysing BMAA in biological samples also inferred method development as part of the experimental studies. Investigating the role of BMAA in its producers was another purpose of the thesis, which may be crucial for future management of BMAA-producing cyanobacteria.

By screening natural populations of the major filamentous bloom forming cyanobacteria of the Baltic Sea, we discovered the presence of BMAA throughout the entire summer season of two consecutive years, using a highly specific analytical method (liquid chromatography-tandem mass spectrometry; LC-MS/MS). BMAA was found to bioaccumulate in zooplankton and fish, as well as in mussels and oysters from the Swedish west coast. To improve the understanding of BMAA analyses in natural samples, the formation of carbamate adducts in the presence of bicarbonate was examined. Using two derivatization techniques in combination with LC-MS/MS, we could show that BMAA detection was not hindered by carbamate formation. Exogenously added BMAA inhibited nitrogen fixation in the model cyanobacterium Nostoc sp. PCC 7120, which was also hampered in growth and displayed signs of nitrogen starvation. Finally, BMAA was detected in cerebrospinal fluid in three of 25 Swedish test individuals, and represents the first confirmation of BMAA in the human central nervous system using LC-MS/MS as the primary analytical method. However, the association of BMAA to neurodegenerative diseases could not be verified as BMAA was present in both control individuals (two) and in one ALS-patient. Nevertheless, the finding of a known neurotoxic compound in the human central nervous system is alarming and potential consequences should be investigated.

The discovery of the neurotoxic compound BMAA in Baltic Sea organisms, and in the central nervous system of humans potentially consuming fish from this ecosystem is concerning and warrants continued investigations of BMAA occurrence and human exposure. Further knowledge on the function and regulation of BMAA may help in developing strategies aiming to minimise human exposure.

Place, publisher, year, edition, pages
Stockholm: Department of Ecology, Environment and Plant Sciences, Stockholm University , 2015. , 85 p.
Keyword [en]
β-N-methylamino-L-alanine, BMAA, cyanobacteria, Baltic Sea, blooms, neurotoxin, neurodegenerative diseases, amyotrophic lateral sclerosis, ALS, nitrogenase, nitrogen fixation
National Category
Biological Sciences
Research subject
Plant Physiology
Identifiers
URN: urn:nbn:se:su:diva-118882ISBN: 978-91-7649-142-3 (print)OAI: oai:DiVA.org:su-118882DiVA: diva2:842352
Public defence
2015-09-10, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2015-08-19 Created: 2015-07-16 Last updated: 2015-08-21Bibliographically approved
List of papers
1. Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure
Open this publication in new window or tab >>Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure
Show others...
2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 20, 9252-9257 p.Article in journal (Refereed) Published
Abstract [en]

beta-methylamino-L-alanine (BMAA), a neurotoxic nonprotein amino acid produced by most cyanobacteria, has been proposed to be the causative agent of devastating neurodegenerative diseases on the island of Guam in the Pacific Ocean. Because cyanobacteria are widespread globally, we hypothesized that BMAA might occur and bioaccumulate in other ecosystems. Here we demonstrate, based on a recently developed extraction and HPLC-MS/MS method and long-term monitoring of BMAA in cyanobacterial populations of a temperate aquatic ecosystem (Baltic Sea, 2007-2008), that BMAA is biosynthesized by cyanobacterial genera dominating the massive surface blooms of this water body. BMAA also was found at higher concentrations in organisms of higher trophic levels that directly or indirectly feed on cyanobacteria, such as zooplankton and various vertebrates (fish) and invertebrates (mussels, oysters). Pelagic and benthic fish species used for human consumption were included. The highest BMAA levels were detected in the muscle and brain of bottom-dwelling fishes. The discovery of regular biosynthesis of the neurotoxin BMAA in a large temperate aquatic ecosystem combined with its possible transfer and bioaccumulation within major food webs, some ending in human consumption, is alarming and requires attention.

Keyword
beta-methylamino-L-alanine, Baltic Sea, cyanobacteria, liquid chromatography/mass spectrometry, bioaccumulation
National Category
Biological Sciences
Research subject
Plant Physiology
Identifiers
urn:nbn:se:su:diva-50529 (URN)10.1073/pnas.0914417107 (DOI)000277822600043 ()
Note

authorCount :8

Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2017-12-11Bibliographically approved
2. BMAA Inhibits Nitrogen Fixation in the Cyanobacterium Nostoc sp PCC 7120
Open this publication in new window or tab >>BMAA Inhibits Nitrogen Fixation in the Cyanobacterium Nostoc sp PCC 7120
Show others...
2013 (English)In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 11, no 8, 3091-3108 p.Article in journal (Refereed) Published
Abstract [en]

Cyanobacteria produce a range of secondary metabolites, one being the neurotoxic non-protein amino acid beta-N-methylamino-L-alanine (BMAA), proposed to be a causative agent of human neurodegeneration. As for most cyanotoxins, the function of BMAA in cyanobacteria is unknown. Here, we examined the effects of BMAA on the physiology of the filamentous nitrogen-fixing cyanobacterium Nostoc sp. PCC 7120. Our data show that exogenously applied BMAA rapidly inhibits nitrogenase activity (acetylene reduction assay), even at micromolar concentrations, and that the inhibition was considerably more severe than that induced by combined nitrogen sources and most other amino acids. BMAA also caused growth arrest and massive cellular glycogen accumulation, as observed by electron microscopy. With nitrogen fixation being a process highly sensitive to oxygen species we propose that the BMAA effects found here may be related to the production of reactive oxygen species, as reported for other organisms.

Keyword
cyanobacteria, toxin, BMAA, Nostoc sp PCC 7120, nitrogen fixation, nitrogenase activity
National Category
Biological Sciences
Research subject
Plant Physiology
Identifiers
urn:nbn:se:su:diva-101500 (URN)10.3390/md11083091 (DOI)000330521300026 ()
Note

AuthorCount:6;

Available from: 2014-03-12 Created: 2014-03-10 Last updated: 2017-12-05Bibliographically approved
3. Effects of bicarbonate on LC-MS/MS analysis of BMAA using AQC or EZ: FaastTM pre-column derivatization
Open this publication in new window or tab >>Effects of bicarbonate on LC-MS/MS analysis of BMAA using AQC or EZ: FaastTM pre-column derivatization
(English)Manuscript (preprint) (Other academic)
Keyword
β-N-methylamino-L-alanine, BMAA, carbamates, bicarbonate, derivatization, AQC, EZ:Faast, LC-MS/MS
National Category
Biological Sciences
Research subject
Plant Physiology
Identifiers
urn:nbn:se:su:diva-118886 (URN)
Available from: 2015-07-19 Created: 2015-07-17 Last updated: 2016-01-29Bibliographically approved
4. DETECTION OF BMAA IN THE HUMAN CENTRAL NERVOUS SYSTEM
Open this publication in new window or tab >>DETECTION OF BMAA IN THE HUMAN CENTRAL NERVOUS SYSTEM
2015 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 292, 137-147 p.Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is an extremely devastating neurodegenerative disease with an obscure etiology. The amino acid beta-N-methyl-L-alanine (BMAA) produced by globally widespread phytoplankton has been implicated in the etiology of human motor neuron diseases. BMAA was recently proven to be present in Baltic Sea food webs, ranging from plankton to larger Baltic Sea organisms, some serving as important food items (fish) for humans. To test whether exposure to BMAA in a Baltic Sea setting is reflected in humans, blood and cerebrospinal fluid (CSF) from individuals suffering from ALS were analyzed, together with sex- and age-matched individuals not inflicted with ALS. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and multiple reaction monitoring (MRM), in conjunction with diagnostic transitions revealed BMAA in three (12%) of the totally 25 Swedish individuals tested, with no preference for those suffering from ALS. The three BMAA-positive samples were all retrieved from the CSF, while BMAA was not detected in the blood. The data show that BMAA, potentially originating from Baltic Sea phytoplankton, may reach the human central nervous system, but does not lend support to the notion that BMAA is resident specifically in ALS-patients. However, while dietary exposure to BMAA may be intermittent and, if so, difficult to detect, our data provide the first demonstration of BMAA in the central nervous system of human individuals ante mortem quantified with UHPLC-MS/MS, and therefore calls for extended research efforts.

Keyword
neurotoxin, BMAA, neurodegeneration, ALS, CSF, blood
National Category
Neurosciences Biological Sciences
Research subject
Plant Physiology
Identifiers
urn:nbn:se:su:diva-116750 (URN)10.1016/j.neuroscience.2015.02.032 (DOI)000351664700013 ()25725357 (PubMedID)
Note

AuthorCount:4;

Available from: 2015-05-12 Created: 2015-04-27 Last updated: 2017-12-04Bibliographically approved

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