Jackson, WY, United States
Jackson, WY, United States

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Bradley W.G.,University of Miami | Borenstein A.R.,University of South Florida | Nelson L.M.,Stanford University | Codd G.A.,University of Stirling | And 2 more authors.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration | Year: 2013

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5-10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L- alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals. © 2013 Informa Healthcare.


Dunlop R.A.,University of Technology, Sydney | Cox P.A.,Institute for Ethnomedicine | Banack S.A.,Institute for Ethnomedicine | Rodgers K.J.,University of Technology, Sydney
PLoS ONE | Year: 2013

Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNAAla with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of l-serine into human proteins. We also report that this misincorporation can be inhibited by l-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS. © 2013 Dunlop et al.


Scott L.L.,Nelson Mandela Metropolitan University | Downing S.,Nelson Mandela Metropolitan University | Phelan R.R.,Nelson Mandela Metropolitan University | Downing T.G.,Nelson Mandela Metropolitan University | Downing T.G.,Institute for Ethnomedicine
Toxicon | Year: 2014

The most significant modulators of the cyanotoxins microcystin and β-N-methylamino-l-alanine in laboratory cyanobacterial cultures are the concentration of growth-medium combined nitrogen and nitrogen uptake rate. The lack of field studies that support these observations led us to investigate the cellular content of these cyanotoxins in cyanobacterial bloom material isolated from a freshwater impoundment and to compare these to the combined nitrogen availability. We established that these toxins typically occur in an inverse relationship in nature and that their presence is mainly dependent on the environmental combined nitrogen concentration, with cellular microcystin present at exogenous combined nitrogen concentrations of 29 μM and higher and cellular BMAA correlating negatively with exogenous nitrogen at concentrations below 40 μM. Furthermore, opposing nutrient and light gradients that form in dense cyanobacterial blooms may result in both microcystin and BMAA being present at a single sampling site. © 2014 Elsevier Ltd. All rights reserved.


Banack S.A.,Institute for Ethnomedicine | Metcalf J.S.,Institute for Ethnomedicine | Jiang L.,University of Stockholm | Craighead D.,Craighead Beringia South | And 2 more authors.
PLoS ONE | Year: 2012

Prior to the evolution of DNA-based organisms on earth over 3.5 billion years ago it is hypothesized that RNA was the primary genetic molecule. Before RNA-based organisms arose, peptide nucleic acids may have been used to transmit genetic information by the earliest forms of life on earth. We discovered that cyanobacteria produce N-(2-aminoethyl)glycine (AEG), a backbone for peptide nucleic acids. We detected AEG in axenic strains of cyanobacteria with an average concentration of 1 μg/g. We also detected AEG in environmental samples of cyanobacteria as both a free or weakly bound molecule and a tightly bound form released by acid hydrolysis, at concentrations ranging from not detected to 34 μg/g. The production of AEG by diverse taxa of cyanobacteria suggests that AEG may be a primitive feature which arose early in the evolution of life on earth. © 2012 Banack et al.


Glover W.B.,University of British Columbia | Liberto C.M.,University of British Columbia | McNeil W.S.,University of British Columbia | Banack S.A.,Institute for Ethnomedicine | And 2 more authors.
Analytical Chemistry | Year: 2012

β-methylamino-l-alanine (BMAA) is a naturally occurring nonprotein amino acid originally discovered in cycad seeds and traditional foods of the Chamorro people of Guam. Recent research has implicated BMAA as a potential factor in neurodegenerative disease and described the production of BMAA in cyanobacteria, but conflicting results have complicated the interpretation of data. We hypothesized that the reactivity of BMAA with metal ions in the sample matrix and the formation of metal adducts in electrospray ionization mass spectrometry (MS) analysis confound results. Dilute solutions of TCA, MgCl 2, NaCl, CuCl2, ZnCl2 (0.01 M), or artificial ocean water (Instant Ocean, 3.5 g/L) reduced the signal attributable to the BMAA M + H+ peak by 78-99.7%. The degree of adduct formation was significantly affected by MS settings such as induction voltage. A number of the detected ion peaks in BMAA standards were consistent with the formation of metal-BMAA complexes in addition to the adduct formation. A standard of Zn(BMAA)2 was synthesized, and the effects of sample preparation, derivatization, column chromatography, pH, and interactions with serine were determined. Together, these data demonstrate that sample matrix, formation of adducts, and mass spectrometry settings complicate analysis of BMAA, that analysis by detection of the parent ion and daughter ion fragmentation patterns are highly susceptible to false negative findings, and that failure to detect BMAA cannot be considered proof of absence of the compound. © 2012 American Chemical Society.


Banack S.A.,Institute for Ethnomedicine | Metcalf J.S.,Institute for Ethnomedicine | Bradley W.G.,University of Miami | Cox P.A.,Institute for Ethnomedicine
Toxicon | Year: 2014

Cyanobacteria produce the neurotoxic amino acid β-N-methylamino-l- alanine (BMAA), which in contaminated marine waters has been found to accumulate in shellfish. Exposure to BMAA has been associated with an increased risk of neurodegenerative disease. Analysis of blinded samples found BMAA to be present in neuroproteins of individuals who died from ALS and ALS/PDC, but generally not in the brains of patients who died of causes unrelated to neurodegeneration or Huntington's disease, an autosomal dominant neurodegenerative disease. We here report support for a link between a patient with ALS and chronic exposure to the cyanobacterial neurotoxin BMAA via shellfish consumption. The patient had frequently eaten lobsters collected in Florida Bay for approximately 30 years. LC-MS/MS analysis of two lobsters which this ALS patient had placed in his freezer revealed BMAA at concentrations of 27 and 4 μg/g, respectively, as well as the presence of 2,4-diaminobutyric acid (DAB), a BMAA isomer. Two additional lobsters recently collected from Florida Bay also contained the neurotoxins BMAA and DAB. These data suggest that invertebrates collected in water where cyanobacterial blooms are present, if consumed, may result in direct human exposure to these neurotoxic amino acids. The data support the assertion that prolonged exposure to BMAA may have played a role in the etiology of ALS in this patient. © 2014 Elsevier Ltd. All rights reserved.


Metcalf J.S.,Institute for Ethnomedicine | Banack S.A.,Institute for Ethnomedicine | Richer R.,Institute for Ethnomedicine | Cox P.A.,Institute for Ethnomedicine
Journal of Arid Environments | Year: 2014

Cyanobacteria are capable of producing a wide range of bioactive compounds including highly toxic molecules which affect a variety of molecular targets. These toxins are well known from aquatic environments, and their occurrence in terrestrial environments is now gaining attention. Of the toxins produced by cyanobacteria, β-N-methylamino-l-alanine (BMAA) is a neurotoxic amino acid linked to human neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's and Parkinson's disease. Two isomers of BMAA are known to be produced by cyanobacteria in axenic culture and in cyanobacterial blooms. Desert crust material was assessed for the presence of BMAA isomers. In addition to BMAA, 2,4-diaminobutyric acid (DAB) and N-(2-aminoethyl)glycine (AEG), were found to be present in desert environments. Both BMAA and DAB are known to be toxic. A preliminary assessment of AEG toxicity was performed with Artemia salina. At high concentrations, AEG was shown to cause mortality of A. salina with paralysis observed at lower concentrations. These findings show that the co-occurrence of BMAA, DAB and AEG may lead to adverse human and animal health effects and future research should consider the interaction of these three isomers for their effect on human health in arid environments. © 2014 Elsevier Ltd. All rights reserved.


Mondo K.,University of Miami | Hammerschlag N.,University of Miami | Basile M.,University of Miami | Pablo J.,University of Miami | And 2 more authors.
Marine Drugs | Year: 2012

Sharks are among the most threatened groups of marine species. Populations are declining globally to support the growing demand for shark fin soup. Sharks are known to bioaccumulate toxins that may pose health risks to consumers of shark products. The feeding habits of sharks are varied, including fish, mammals, crustaceans and plankton. The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) has been detected in species of free-living marine cyanobacteria and may bioaccumulate in the marine food web. In this study, we sampled fin clips from seven different species of sharks in South Florida to survey the occurrence of BMAA using HPLC-FD and Triple Quadrupole LC/MS/MS methods. BMAA was detected in the fins of all species examined with concentrations ranging from 144 to 1836 ng/mg wet weight. Since BMAA has been linked to neurodegenerative diseases, these results may have important relevance to human health. We suggest that consumption of shark fins may increase the risk for human exposure to the cyanobacterial neurotoxin BMAA.


Metcalf J.S.,University of Dundee | Metcalf J.S.,Institute for Ethnomedicine | Metcalf J.S.,University of Mississippi | Richer R.,Cornell College | And 2 more authors.
Science of the Total Environment | Year: 2012

There have been few studies concerning cyanotoxins in desert environments, compared with the multitude of studies of cyanotoxins in aquatic environments. However, cyanobacteria are important primary producers in desert environments, where after seasonal rains they can grow rapidly both stabilising and fertilising arid habitats. Samples of cyanobacteria from wadis - dry, ephemeral river beds - and sabkha - supertidal salt flats - in Qatar were analysed for the presence of microcystins, nodularin, anatoxin-a, cylindrospermopsin and anatoxin-a(S). Microcystins were detected by HPLC-PDA and ELISA at concentrations between 1.5 and 53.7ngg -1 dry wt of crust. PCR products for the mycD gene for microcystin biosynthesis were detected after amplification of DNA from desert crust samples at two out of three sample sites. The presence of anatoxin-a(S) was also indicated by acetylcholine esterase inhibition assay. As a function of area of desert crust, microcystin concentrations were between 3 and 56μgm -2. Based on the concentration of microcystins detected in crust, with reference to the published inhalation NOAEL and LOAEL values via nasal spray inhalation of purified microcystin-LR in aqueous solution, and the amount of dust potentially inhaled by a person from these dried crusts, the dose of microcystins could exceed a calculated TDI value of 1-2ngkg -1day -1 for an average adult. The presence of microcystins, and potentially of anatoxin-a(S), in desert crusts has important implications for human health. Further studies are required to monitor desert dust storms for the presence of cyanotoxins. An understanding of the risks of inhaling particles containing cyanotoxins is also warranted. © 2012 Elsevier B.V.


Field N.C.,Dartmouth Hitchcock Medical Center | Metcalf J.S.,Institute for Ethnomedicine | Caller T.A.,Dartmouth Hitchcock Medical Center | Banack S.A.,Institute for Ethnomedicine | And 2 more authors.
Toxicon | Year: 2013

Most amyotrophic lateral sclerosis (ALS) cases occur sporadically. Some environmental triggers have been implicated, including beta-methylamino-. l-alanine (BMAA), a cyanobacteria produced neurotoxin. This study aimed to identify environmental risk factors common to three sporadic ALS patients who lived in Annapolis, Maryland, USA and developed the disease within a relatively short time and within close proximity to each other. A questionnaire was used to identify potential risk factors for ALS among the cohort of patients. One common factor among the ALS patients was the frequent consumption of blue crab. Samples of blue crab from the patients' local fish market were tested for BMAA using LC-MS/MS. BMAA was identified in these Chesapeake Bay blue crabs. We conclude that the presence of BMAA in the Chesapeake Bay food web and the lifetime consumption of blue crab contaminated with BMAA may be a common risk factor for sporadic ALS in all three patients. © 2013 Elsevier Ltd.

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