Special Issue "The Cyanobacterial Neurotoxin BMAA"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Marine and Freshwater Toxins".

Deadline for manuscript submissions: closed (31 December 2017).

Special Issue Editor

Prof. Tim Downing

Guest Editor
Biochemistry and Microbiology, Nelson Mandela Metropolitan University

Special Issue Information

Dear Colleagues,

The cyanobacterial metabolite β-N-methylamino-L-alanine (BMAA) has been proposed as a causative or contributory factor in the development of non-familial neurodegenerative diseases. The origin of this proposed link, commonly referred to as “The BMAA Hypothesis”, is the discovery of the amino acid BMAA as a component of the diet of the Chamorro people of Guam, who suffered from a very high incidence of Amyotrophic Lateral Sclerosis—Parkinsonism—Dementia Complex (ALS/PDC). Subsequent reports of BMAA in brain tissue of ALS/PDC and Alzheimer’s disease victims, appeared to support the hypothesis, and a relatively large body of in vitro and animal work, demonstrating acute neurotoxicity, was published, albeit at environmentally irrelevant exposure concentrations. Chronic animal exposure data are limited to a few reports, with at most a few months of exposure, and also at concentrations too high to represent environmental exposure. The absence of neuropathology or symptoms at environmentally relevant doses is one of the factors challenging the hypothesis. The environmental prevalence and potential human exposure risk also remain controversial topics, with widely disparate data in the literature both on the quantities of BMAA in the environment and the potential for exposure via inhalation and ingestion, and although an effort has been made to find spatial correlations between BMAA exposure and higher incidence of ALS, the low incidence of sporadic ALS makes finding adequate cases for such a study challenging. Research data on the potential link between cyanobacterial or BMAA exposure and either Alzheimer’s disease of Parkinson’s disease is absent in literature. The other vital component to support the BMAA hypothesis, is clarity on the mechanism of toxicity. Excitotoxicity and protein misincorporation have been suggested as mechanisms of toxicity, and although relatively weak excitotoxicity has been demonstrated for BMAA, misincorporation remains hypothetical. An understanding of how the exposure route or age, or exposure dose or dose regime, the systemic distribution and metabolic fate of BMAA, and the specific mechanism or mechanisms of toxicity, can result in the neuropathology and symptoms at the observed incidence of the relevant neurodegenerative diseases, is necessary to substantiate the link between BMAA and these diseases. The purpose of this Special Issue is therefore to highlight current research relevant to this link by focusing on environmental BMAA exposure route and exposure concentration, the geospatial link between exposure and disease, the systemic distribution and metabolic fate of ingested or inhaled BMAA, and the proposed mechanisms of BMAA neurotoxicity and associated pathologies in any model system. Manuscripts related to BMAA toxicology are therefore invited from all related fields and disciplines.

Prof. Dr. Tim Downing
Guest Editor

Note added by the Publisher: the Guest Editor was not involved in the editorial process for manuscripts on which they are authors. In this case, the editorial decisions were done by independent editorial board members.

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • BMAA
  • β-N-methylamino-L-alanine
  • exposure
  • neurotoxicity
  • neuropathology
  • ALS
  • ALS/PDC
  • neurodegeneration

Published Papers (5 papers)

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Research

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Open AccessFeature PaperArticle
A Single Neonatal Exposure to BMAA in a Rat Model Produces Neuropathology Consistent with Neurodegenerative Diseases
Toxins 2018, 10(1), 22; https://doi.org/10.3390/toxins10010022 - 29 Dec 2017
Cited by 15
Abstract
Although cyanobacterial β-N-methylamino-l-alanine (BMAA) has been implicated in the development of Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS), no BMAA animal model has reproduced all the neuropathology typically associated with these neurodegenerative diseases. We present [...] Read more.
Although cyanobacterial β-N-methylamino-l-alanine (BMAA) has been implicated in the development of Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS), no BMAA animal model has reproduced all the neuropathology typically associated with these neurodegenerative diseases. We present here a neonatal BMAA model that causes β-amyloid deposition, neurofibrillary tangles of hyper-phosphorylated tau, TDP-43 inclusions, Lewy bodies, microbleeds and microgliosis as well as severe neuronal loss in the hippocampus, striatum, substantia nigra pars compacta, and ventral horn of the spinal cord in rats following a single BMAA exposure. We also report here that BMAA exposure on particularly PND3, but also PND4 and 5, the critical period of neurogenesis in the rodent brain, is substantially more toxic than exposure to BMAA on G14, PND6, 7 and 10 which suggests that BMAA could potentially interfere with neonatal neurogenesis in rats. The observed selective toxicity of BMAA during neurogenesis and, in particular, the observed pattern of neuronal loss observed in BMAA-exposed rats suggest that BMAA elicits its effect by altering dopamine and/or serotonin signaling in rats. Full article
(This article belongs to the Special Issue The Cyanobacterial Neurotoxin BMAA)
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Open AccessFeature PaperArticle
β-N-Methylamino-L-alanine (BMAA) Toxicity Is Gender and Exposure-Age Dependent in Rats
Toxins 2018, 10(1), 16; https://doi.org/10.3390/toxins10010016 - 27 Dec 2017
Cited by 7
Abstract
Cyanobacterial β-N-methylamino-L-alanine (BMAA) has been suggested as a causative or contributory factor in the development of several neurodegenerative diseases. However, no BMAA animal model has adequately shown clinical or behavioral symptoms that correspond to those seen in either Alzheimer’s [...] Read more.
Cyanobacterial β-N-methylamino-L-alanine (BMAA) has been suggested as a causative or contributory factor in the development of several neurodegenerative diseases. However, no BMAA animal model has adequately shown clinical or behavioral symptoms that correspond to those seen in either Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS) or Parkinson’s Disease (PD). We present here the first data that show that when neonatal rats were exposed to BMAA on postnatal days 3, 4 and 5, but not on gestational day 14 or postnatally on days 7 or 10, several AD and/or PD-related behavioral, locomotor and cognitive deficits developed. Male rats exhibited severe unilateral hindlimb splay while whole body tremors could be observed in exposed female rats. BMAA-exposed rats failed to identify and discriminate a learned odor, an early non-motor symptom of PD, and exhibited decreased locomotor activity, decreased exploration and increased anxiety in the open field test. Alterations were also observed in the rats’ natural passive defense mechanism, and potential memory deficits and changes to the rat’s natural height avoidance behavior could be observed as early as PND 30. Spatial learning, short-term working, reference and long-term memory were also impaired in 90-day-old rats that had been exposed to a single dose of BMAA on PND 3–7. These data suggest that BMAA is a developmental neurotoxin, with specific target areas in the brain and spinal cord. Full article
(This article belongs to the Special Issue The Cyanobacterial Neurotoxin BMAA)
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Open AccessFeature PaperArticle
Human Scalp Hair as an Indicator of Exposure to the Environmental Toxin β-N-Methylamino-l-alanine
Toxins 2018, 10(1), 14; https://doi.org/10.3390/toxins10010014 - 27 Dec 2017
Cited by 4
Abstract
Dietary or aerosol exposure to the environmental neurotoxin β-N-methylamino-l-alanine (BMAA) is a putative risk factor for the development of sporadic neurodegenerative disease. There are many potential sources of BMAA in the environment, but BMAA presence and quantities are highly [...] Read more.
Dietary or aerosol exposure to the environmental neurotoxin β-N-methylamino-l-alanine (BMAA) is a putative risk factor for the development of sporadic neurodegenerative disease. There are many potential sources of BMAA in the environment, but BMAA presence and quantities are highly variable. It has been suggested that BMAA in human hair may serve as an indicator of exposure. We sought to evaluate the use of the BMAA content of human scalp hair as an indicator of exposure, as well as the correlation between specific lifestyle or dietary habits, reported as hypothesised exposure risk factors, and BMAA in hair. Scalp hair samples and questionnaires were collected from participants in a small residential village surrounding a freshwater impoundment renowned for toxic cyanobacterial blooms. Data suggested a positive correlation between hair BMAA content and consumption of shellfish, and possibly pork. No statistically significant correlations were observed between hair BMAA content and residential proximity to the water or any other variable. Hair BMAA content was highly variable, and in terms of exposure, probably reflects primarily dietary exposure. However, the BMAA content of human hair may be affected to a great extent by several other factors, and as such, should be used with caution when evaluating human BMAA exposure, or correlating exposure to neurodegenerative disease incidence. Full article
(This article belongs to the Special Issue The Cyanobacterial Neurotoxin BMAA)
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Open AccessArticle
Investigating β-N-Methylamino-l-alanine Misincorporation in Human Cell Cultures: A Comparative Study with Known Amino Acid Analogues
Toxins 2017, 9(12), 400; https://doi.org/10.3390/toxins9120400 - 14 Dec 2017
Cited by 12
Abstract
Misincorporation of β-N-methylamino-l-alanine (BMAA) into proteins has been proposed to be a mechanism of toxicity to explain the role of BMAA in neurodegenerative disease development. However, studies have shown that all detectable BMAA can be removed from proteins by [...] Read more.
Misincorporation of β-N-methylamino-l-alanine (BMAA) into proteins has been proposed to be a mechanism of toxicity to explain the role of BMAA in neurodegenerative disease development. However, studies have shown that all detectable BMAA can be removed from proteins by SDS-PAGE purification and that the toxicity of l-canavanine cannot be reproduced in prokaryotes or in a rat pheochromocytoma cell line, strongly indicating that the misincorporation hypothesis of BMAA should be re-investigated. The aim of this study was therefore to determine if BMAA misincorporates into proteins in cells of human origin with subsequent misincorporation-type toxicity. Almost complete loss of viability in response to exposure to l-4-fluorophenylalanine and l-m-tyrosine was observed in all of the cell lines, corresponding to a concentration-dependent increase of the analogues in protein extracts from exposed cells. In contrast, BMAA exposure resulted in slight toxicity in one of the cell lines but the observed toxicity was not the result of misincorporation of BMAA into proteins, as no BMAA was detected in any of the SDS-PAGE purified protein extracts that were obtained from the cells following BMAA exposure. The results show that BMAA is not misincorporated into human proteins and that misincorporation is not a valid mechanism of toxicity. Full article
(This article belongs to the Special Issue The Cyanobacterial Neurotoxin BMAA)
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Review

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Open AccessReview
Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy
Toxins 2018, 10(1), 6; https://doi.org/10.3390/toxins10010006 - 22 Dec 2017
Cited by 11
Abstract
The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA) in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis [...] Read more.
The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA) in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS) and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA-induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes. Full article
(This article belongs to the Special Issue The Cyanobacterial Neurotoxin BMAA)
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