Cyanobacteria

the common name for cyanobacteria is blue-green algae. However, cyanobacteria are related more closely
to bacteria than to algae.

Scientists have called cyanobacteria the origin of plants, and have credited cyanobacteria with providing nitrogen
fertilizer for rice and beans.

Freshwater CyanoHABs can use up the oxygen and block the sunlight that other organisms need to live. They also can
produce powerful toxins that affect the brain and liver of animals and humans. Because of concerns about CyanoHABs,
which can grow in drinking water and recreational water, the U.S. Environmental Protection Agency (EPA) has added
cyanobacteria to its Drinking Water Contaminant Candidate List. This list identifies organisms and toxins that EPA
considers to be priorities for investigation.

Humans can be exposed to cyanobacterial toxins by drinking water that contains the toxins, swimming in water that
contains high concentrations of cyanobacterial cells, or breathing air that contains cyanobacterial cells or toxins (while
watering a lawn with contaminated water, for example).

Health effects associated with exposure to high concentrations of cyanobacterial toxins include:

stomach and intestinal illness;
trouble breathing;
allergic responses;
skin irritation;
liver damage; and
neurotoxic reactions, such as tingling fingers and toes.

Scientists are exploring the human health effects associated with long-term exposure to low levels of cyanobacterial
toxins. Some studies have suggested that such exposure could be associated with chronic illnesses, such as liver
cancer and digestive-system cancer.
http://www.cdc.gov/hab/cyanobacteria/about.htm



Some cyanobacteria that can form CyanoHABs produce toxins that are among the most powerful natural poisons
known. These toxins have no known antidotes.  CyanoHABs can make people, their pets, and other animals sick. Often,
the first sign that an HAB exists is a sick dog that has been swimming in an algae-filled pond.  Children are at higher risk
than adults for illness from CyanoHABs because they weigh less and can get a relatively larger dose of toxin.

Cyanotoxins Cyanotoxins are a diverse group of chemical substances that are categorized by their specific toxic effects
as follows:  Neurotoxins affect the nervous system. Anatoxin-a  Anatoxin-a(s)  Saxitoxin  Neosaxitoxin  Hepatotoxins
affect the liver. Microcystins  Nodularins  Cylindrospermopsin  Tumor promoters are chemicals that can increase tumor
growth. Microcystins  Lipopolysaccharides are chemicals that can affect the gastrointestinal system.  See Table 1
[opens in new window] for a list of cyanotoxins and their specific toxic mechanisms, their effects, the symptoms they
cause, and treatments for poisoning.

How you could be exposed to CyanoHABs and cyanotoxins Drinking water that comes from a lake or reservoir with a
CyanoHAB.  Drinking untreated water.  Engaging in recreational activities in waters with CyanoHABs.  Inhaling aerosols
from water-related activities such as jet-skiing or boating.  Inhaling aerosols when watering lawns, irrigating
golf-courses, etc. with pond water.  Using cyanobacteria-based dietary supplements that are contaminated with
microcystins.  Receiving dialysis (this has been documented only in Brazil).

Types of illnesses people and animals can get from exposure to CyanoHABs
Getting it on the skin may give people a rash, hives, or skin blisters (especially on the lips and under swimsuits).
Inhaling water droplets from irrigation or water-related recreational activities can cause runny eyes and nose, a sore
throat, asthma-like symptoms, or allergic reactions.
Swallowing water that has cyanobacterial toxins in it can cause
Acute, severe gastroenteritis (including diarrhea and vomiting).
Liver toxicity (i.e., increased serum levels of liver enzymes). Symptoms of liver poisoning may takes hours or days to
show up in people or animals. Symptoms include abdominal pain, diarrhea, and vomiting.
Kidney toxicity.
Neurotoxicity. These symptoms can appear within 15 to 20 minutes after exposure. In dogs, the neurotoxins can cause
salivation and other neurologic symptoms, including weakness, staggering, difficulty breathing, convulsions, and death.
People may have numb lips, tingling fingers and toes, or they may feel dizzy.
http://www.cdc.gov/hab/cyanobacteria/facts.htm#exposure


March 2012
The Emerging Science of BMAA: Do Cyanobacteria Contribute to Neurodegenerative Disease?

http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.120-a110


Excerpts:
Cyanobacteria [which can cause ALS and dementia] either form symbiotic relationships with other organisms or live
alone in fresh and marine waters, where they can erupt in sprawling and often toxic blooms associated with high nutrient
inputs such as fertilizer runoff.


It could mean a paradigm shift for a field that has invested a lot of money studying the genetics of ALS rather than
environmental triggers.


Only 5-10% of ALS, AD, and Parkinson disease (PD) cases are due to inherited genetic mutations, says Walter Bradley,
an ALS expert and former chairman of neurology
at the University of Miami Miller School of Medicine. "Hundreds of millions of dollars have been spent looking for
predisposing genes, but . . . there is really a need to concentrate much more on environmental toxicants," Bradley says.


BMAA and methylmercury-a common pollutant in seafood-both deplete glutathione, the main endogenous antioxidant in
the body, and they act synergistically to harm nerve cells.47,48 Depletion of glutathione increases free radical damage
that is known to occur in neurodegenerative diseases and has been linked to ALS in a transgenic SOD1 mouse model,
says Lobner.49 Because BMAA and methylmercury can both turn up in waterways, this synergistic action could pose a
grave problem.


Species low on the food chain, including pink shrimp and blue crab-both of which are eaten by humans-had high BMAA
levels, comparable to the bat skins from Guam (one crab had 6,976 µg/g).51 Mash's laboratory has also found BMAA in
several shark species in unpublished research. Brand wants to test farm-raised shrimp since, he says, they grow in
ponds flush with cyanobacteria.


Some agricultural fields are irrigated from water bodies covered in cyanobacterial blooms, raising the potential that
BMAA could get into milk, meat, or vegetables.


"We encourage water managers to take a closer look at cyanobacterial blooms," he says. "We need to encourage
places where there are commercial shellfish fisheries to pay attention to water quality."


...investigating high BMAA levels in oysters off the coast of southern France, where an ALS cluster occurs.




The Emerging Science of BMAA: Do Cyanobacteria Contribute to Neurodegenerative Disease?
Wendee Holtcamp
Houston-based freelancer Wendee Holtcamp has written for Nature, Scientific American, National Wildlife, and other
magazines.

Citation: Holtcamp W 2012. The Emerging Science of BMAA: Do Cyanobacteria Contribute to Neurodegenerative
Disease? Environ Health Perspect 120:a110-a116. http://dx.doi.org/10.1289/ehp.120-a110

Online: 01 March 2012

In the late 1990s ethnobotanist Paul Alan Cox visited the indigenous Chamorro people of Guam, sleuthing for cancer
cures in the lush rainforest. He soon stumbled upon troubling facts that would change the trajectory of his career,
leading to major clues in understanding Lou Gehrig's disease (amyotrophic lateral sclerosis, or ALS) and possibly other
neurodegenerative diseases. Since that time, major breakthroughs in the fields of neurobiology, epidemiology, and
ecology have led to an increased interest in an unlikely hypothesis: that ?-methylamino-?-alanine (BMAA)-a
cyanobacterial neurotoxin found in contaminated seafood and shellfish, drinking water supplies, and recreational
waters-may be a major factor in these diseases.

Last fall, writer Wendee Holtcamp visited Paul Cox's Institute for EthnoMedicine and Yellowstone National Park's Grand
Prismatic Spring, named for the vividly colored cyanobacteria that live along the spring's edge. She also kayaked on
Lake Houston to collect water and sediment, which Cox's group tested for BMAA. The results of that test were described
in the January/February 2012 issue of Miller-McCune Magazine.55


A Trail of Clues
The trail of clues began soon after U.S. forces recaptured Guam from the Japanese in 1944. A Navy neurologist noticed
the Chamorro people succumbed to a strange neurodegenerative illness that caused paralysis, shaking, and dementia
at 50-100 times the incidence of ALS worldwide.1,2 The illness was dubbed amyotrophic lateral
sclerosis-parkinsonism/dementia complex (ALS-PDC), known locally as lytico-bodig. Since then, neurologists have
converged on the island to crack the medical version of the world's hardest math problem. Solving the mystery of this
many-faceted illness, it was hoped, could unlock a deeper understanding of neurodegenerative diseases worldwide and
possibly lead to a cure.

BMAA was first isolated from cycad trees on Guam in 1967. The discovery was serendipitous, an offshoot of research
on lathyrism, a progressive paralysis of the legs found in people in China, India, and the Middle East. Studies had linked
lathyrism to consumption of certain species of legumes that contained the compound ?-N-oxalylamino-?-alanine
(BOAA).3 Marjorie Whiting, a nutritional anthropologist working on Guam for the National Institutes of Health, recognized
a similarity between lathyrism and ALS-PDC and asked Arthur Bell, a noted plant biochemist and director of the Kew
Royal Botanic Gardens, to test cycad seeds for BOAA. Although the cycads didn't contain BOAA, Bell discovered a
similar compound with a methyl group instead of an oxalyl group-BMAA.4,5

Subsequent research showed that BMAA caused convulsions in chicks6 and rats7 and damaged rat neurons.8
However, dietary exposure did not cause delayed symptoms in rats,7 whereas ALS-PDC, it soon became clear,
developed years or even decades after exposure ceased. In the 1980s Peter Spencer, then a neurotoxicologist at the
Albert Einstein College of Medicine, briefly resurrected the BMAA hypothesis and reported shaking and paralysis in
macaques fed BMAA,9 but his work was heavily criticized by another team of neurologists that argued that people would
have to eat kilograms of cycad flour to ingest a comparable dose.10
Cox arrived in Guam in the late 1990s after the trail had run cold, but through a series of discoveries, he resurrected
the dormant hypothesis that BMAA was the cause behind ALS-PDC. The Chamorro made tortillas out of ground cycad
seeds, which they washed repeatedly to remove toxins (if their chickens didn't die after drinking the wash water, the
people deemed the seeds safe to grind and eat). They also ate feral pigs and fruit bats that fed on cycad seeds-the
bats, known as Mariana flying foxes, were stewed in coconut cream and eaten whole-brains, bones, skin, and all. In
2002 Cox and Columbia University Medical Center neurologist Oliver Sacks hypothesized that chronic dietary exposure
creates a neurotoxic reservoir of BMAA in the brain tissues of the Chamorros that, after a lag time, leads to a neuronal
meltdown.11 The breakthroughs that would expand the story beyond Guam were soon to come.


BMAA is produced by 95% of the genera of cyanobacteria tested, including Nostoc, which grows in the roots of the
cycad tree and appears as the green lining in the cutaway roots pictured above.
Molecular structure: © Scimat/Photo Researchers, Inc.; all other images: Paul A. Cox

Cox's colleague Sandra Banack, then a biology professor at California State University, Fullerton, was working with Cox
in Hawaii analyzing Mariana flying fox skins to determine whether they contained BMAA. "We decided if [BMAA] wasn't in
the bats, we'd just move on," says Cox. In a way, Cox says, he hoped BMAA wouldn't be the triggering compound,
remembering the ridicule encountered by Spencer in the 1980s. But one night around 2:00 a.m., he recalls, "Sandra
called me from the lab, and I picked up on the first ring. She said, 'We got it.'"

About the same time, Cox and Banack made another advance, discovering that BMAA was produced by cyanobacteria
that lived as symbionts in specialized roots of the cycads.12 They tested BMAA in various organisms along the food
chain and found samples of Mariana flying fox skin had exorbitant BMAA levels averaging 3,556 µg/g.13 This was
10,000 times more than was found in free-living cyanobacteria and 3 times as much as in the fleshy cycad seed coat
eaten by the bats, supporting the idea of biomagnification (in which a contaminant-usually a fat-soluble
compound-accumulates in an organism).12 But the biggest surprise came when they tested human brains in a blinded
study. They found high BMAA concentrations not just in the brains of all ALS-PDC patients tested but also in the brains
of Canadians who died of Alzheimer disease (AD)-yet not in age-matched controls.14 If BMAA was produced by
cyanobacteria on Guam, how could people in Canada be exposed?




A Cyanobacterial Neurotoxin
Because cyanobacteria photosynthesize, scientists once classified them as algae-and many people still refer to them as
blue-green algae-but modern genetics reveals a separate evolutionary lineage. Cyanobacteria either form symbiotic
relationships with other organisms or live alone in fresh and marine waters, where they can erupt in sprawling and often
toxic blooms associated with high nutrient inputs such as fertilizer runoff. They also are found in desert crusts, where
they spring to life with seasonal rains. The incidence of cyanobacterial blooms has increased worldwide and may grow
even more widespread with warming climates.15

In a 2005 article in Proceedings of the National Academy of Sciences, Cox and several colleagues reported testing 30
laboratory strains of cyanobacteria and finding that 95% of the genera tested produced BMAA.16 "We realized that
once we published this result, it was going to shake a lot of trees," says Cox. It could mean a paradigm shift for a field
that has invested a lot of money studying the genetics of ALS rather than environmental triggers.
Only 5-10% of ALS, AD, and Parkinson disease (PD) cases are due to inherited genetic mutations, says Walter Bradley,
an ALS expert and former chairman of neurology
at the University of Miami Miller School of Medicine. "Hundreds of millions of dollars have been spent looking for
predisposing genes, but . . . there is really a need to concentrate much more on environmental toxicants," Bradley says.

"Big Pharma has spent big money to come up with new medications targeted against the best mechanisms that the
scientific community has tested," says Deborah Mash, a neurologist at the University of Miami Miller School of Medicine
and director of the Miami Brain Bank. Collaborating with Bradley, she replicated Cox's brain study, finding BMAA in the
brains of AD, PD, and ALS victims but not in controls.17 She also showed BMAA crosses the blood-brain barrier in rats.
In these studies, they found that the molecule takes longer to get into the brain than into other organs, but once there, it
gets trapped in proteins, forming a reservoir for slow release over time.18,19


The seeds of the cycad are used as food and medicine by the indigenous Chamorro people of Guam. They are also
eaten by bats and feral pigs that are consumed by the Chamorro. The resulting heavy dietary intake of BMAA has been
linked with a constellation of neurodegenerative symptoms known locally as lytico-bodig.
All images: Paul A. Cox

Once Cox realized that BMAA may be involved in multiple neurodegenerative diseases, he left Hawaii to establish the
Institute for EthnoMedicine in Jackson Hole, Wyoming, where he was joined by Banack and later by James Metcalf, a
cyanobacterial expert. While Banack got busy with lab work, Cox raised funds for the institute's research and
established a loose consortium of scientists around the world-epidemiologists, neurobiologists, and ecologists. They
meet once a year to discuss research findings and directions for future research.

Cox has spent the bulk of his research efforts focusing on ALS, in part for humanitarian reasons; ALS strikes healthy,
predominantly middle-aged people seemingly at random, and, of the major neurodegenerative diseases, it has the least
hope for treatment and survival (in clinical trials, the only FDA-approved treatment20 for ALS offered approximately 3
extra months of life, although improved treatment protocols may extend this time).

ALS affects motor neurons, the longest cells in the body. Although mental capabilities stay intact, ALS paralyzes
patients, often from the periphery inward, and most patients die within 3 years when they can no longer breathe or
swallow. At any given time, an estimated 30,000 ALS cases exist in the United States21 (compared with 5.4 million AD
patients22 and 500,000 PD patients23), but lifetime risk in this country is estimated at approximately 1 in 350 for men
and 1 in 450 for women.24 Only 10% of cases are thought to be inherited (these are termed "familial ALS"), with
15-20% of these linked to mutation in the SOD1 (superoxide dismutase) gene.25 The cause of the remaining 90%
(termed "sporadic ALS") remains unexplained.26


Mistakes in Translation
A foundational aspect of Cox's hypothesis-and the part that has proven the most contentious10,27,28,29,30-is that
BMAA not only occurs as a free, water-soluble molecule but also gets bound into proteins. Since hydrolysis is necessary
to release protein-bound BMAA,31 Cox suspects that other studies underestimated or missed BMAA altogether.32,33
BMAA is a nonproteinogenic amino acid, meaning it is not one of the 20 amino acids that make up proteins in all
eukaryotic organisms.
Accumulation of BMAA in the proteins of nerve cells, which need to last a lifetime, would provide a mechanism for how
the toxin might biomagnify. "The problem with neurons is they do not divide, as a general rule, so over time they
accumulate damaged proteins, and once they reach a critical level, it causes the cell to undergo apoptosis [cell death],"
explains Rachael Dunlop, a researcher with the Heart Research Institute in Sydney, Australia.


The genetic code in the messenger RNA holds the "recipe" for constructing a protein, and transfer RNA, which contains
the matching code, attaches the correct amino acid. New research indicates BMAA can bind to serine (SER) transfer
RNA and become part of the protein chain.40
Kenneth Rodgers, Matthew Ray/EHP



Once BMAA is incorporated into the chain, the protein can no longer fold properly. Clumps of misfolded proteins may
form the aggregates that characterize neurodegenerative disease.41
Kenneth Rodgers, Matthew Ray/EHP

In rapidly dividing nonneuronal cells, Dunlop explains, damaged proteins that have formed aggregates are diluted into
daughter cells. "These cells effectively get rid of their 'junk' by dilution," she says. "Neuronal cells can't do that and
eventually get overwhelmed and die." Accumulation could also explain how BMAA could plausibly lead to the telltale
misfolded proteins observed in the brains of those who die of neurodegenerative disease.
But Cox and colleagues had no additional conclusive evidence linking BMAA and protein aggregates in the brain, and
his idea came under fire. "The whole scientific world at that time thought that the machinery of cells would look at
[BMAA] and say, 'That's not one of the twenty [proteinogenic] amino acids,'" says Bradley. Each amino acid has its own
transfer RNA (tRNA) synthetase, a highly specific enzyme that picks up an amino acid and attaches it to the matching
codon on the messenger RNA (mRNA) during translation, an early step in the process of protein synthesis. "There has
been a gradual accumulation of research showing that not only does misincorporation of various nonproteinogenic
amino acids occur, but it also can cause human and animal disease," Bradley says.


In 2006 Susan Ackerman and colleagues published in Nature that misincorporation of the wrong proteinogenic amino
acid, even at the background error rate (1 error per 1,000-10,000 codons), can lead to neurodegeneration in mice.34
Other research has revealed that organisms do, in fact, misincorporate nonproteinogenic amino acids.4,35 In 2002
Kenneth Rodgers, a senior lecturer at the University of Technology, Sydney, found that a range of nonproteinogenic
amino acids can be incorporated into cell proteins by mammalian cells, among them the amino acid levodopa (l-DOPA),
the treatment most commonly used for PD.36 Rodgers subsequently detected l-DOPA in brain proteins of treated PD
patients.37,38 "We have sequenced proteins and shown that l-DOPA is incorporated into proteins in place of
tyrosine,39" says Rodgers, who is now part of Cox's consortium.

Evidence that BMAA isn't just found in brain tissue but actually gets misincorporated into nerve cell proteins and that
this causes protein misfolding and ultimately cell death was presented at the International ALS/Motor Neuron Disease
(MND) Symposium in December 2011.40 Rodgers and Dunlop reported that the tRNA synthetase enzyme for the amino
acid serine mistakenly picks up BMAA and incorporates it into proteins in vitro. Consequent autofluorescence indicated
that the proteins misfolded, and the cells died.41


Multiple Modes of Neurotoxicity
In most proteins, the hydrophilic (water-loving) parts stay on the outside while the hydrophobic (water-repelling) parts
stay on the inside of the structure, but damage or mistakes in translation, such as misincorporation of BMAA, can cause
the hydrophobic parts of the protein to end up exposed. These sticky parts adhere to other misformed proteins, forming
"aggregates," a telltale sign of neurodegenerative disease.42 The formation of small aggregates seeds the formation of
larger, more toxic aggregates in a sort of chain reaction that prevents the cells from functioning effectively.43

Recent ALS research has focused on the role of TAR DNA-binding protein 43 (TDP-43) in neurodegeneration.44
"TDP-43 has been found in protein aggregates from patients affected by both familial and sporadic forms of ALS, so
even without the mutated gene, an improperly functioning TDP-43 can contribute to disease," says Dunlop. "If the
misincorporation of BMAA in place of serine into TDP-43 causes the protein to misfold or not function correctly, this
could contribute to ALS. We are not naïve enough to think this is the only catalyst for sporadic ALS-there are likely
several processes that need to come together to lead to motor neuron dysfunction and eventually death-but it's a clue."

"The recent finding that BMAA is mistaken for serine by tRNA synthetase during protein formation opens up a plethora
of potential new studies in lab models of ALS, from yeast to mice, to see whether the formation of protein
aggregates-the classic 'hallmarks' of motor neuron degeneration-can be replicated," says Brian Dickie, director of
research at the Motor Neurone Disease Association. "We held a similar session at the 2008 ALS/MND Symposium,45
and I was struck by how many more research groups are now working in this field. There is definitely greater
acceptance that this avenue should be pursued."

In addition to protein misincorporation, high levels of unbound BMAA can continually overstimulate glutamate receptors
on cells, leading to neuronal injury.46 Marquette University biology professor Doug Lobner found that BMAA and
methylmercury-a common pollutant in seafood-both deplete glutathione, the main endogenous antioxidant in the body,
and they act synergistically to harm nerve cells.47,48 Depletion of glutathione increases free radical damage that is
known to occur in neurodegenerative diseases and has been linked to ALS in a transgenic SOD1 mouse model, says
Lobner.49 Because BMAA and methylmercury can both turn up in waterways, this synergistic action could pose a grave
problem.
The jury is still out on how multiple variables work together to cause neurodegeneration. "There are genetic variables.
There are environmental variables. There are human health variables. This is probably a smorgasbord of bad things
that occur to you in your life," says Mash. "Maybe it's oxidative stress. Maybe it's BMAA getting misincorporated, and
you're building up a bunch of junky proteins in the cell. And maybe you're putting stress on the mitochondria, and the
mitochondria are making more reactive oxidative species, and now you've got a one-two punch on the cell."


Other Lines of Inquiry
While the mechanisms of BMAA toxicity are being worked out, ecological work has provided other lines of evidence.
Mash collaborated with algal ecologist Larry Brand of the University of Miami Rosenstiel School of Marine and
Atmospheric Science to test for BMAA in sea life from Florida coastal waters, including Florida Bay, which has a massive
recurring cyanobacterial bloom.50 Species low on the food chain, including pink shrimp and blue crab-both of which are
eaten by humans-had high BMAA levels, comparable to the bat skins from Guam (one crab had 6,976 µg/g).51 Mash's
laboratory has also found BMAA in several shark species in unpublished research. Brand wants to test farm-raised
shrimp since, he says, they grow in ponds flush with cyanobacteria.

Preliminary data also revealed BMAA in dolphin brains.52 "We're interested in dolphins because they eat the same kind
of seafood that we do," says Brand. "I was pretty skeptical we'd see anything. From a chemical point of view, you really
would not expect BMAA to biomagnify in the food chain." It turned out 5 of 6 dolphin brains sampled contained BMAA;
however, the cause of death-impact by a boat-was known only for the sixth dolphin, which had no detectable BMAA in its
brain.


An important area of future research involves potential exposure routes in addition to seafood consumption. Some
agricultural fields are irrigated from water bodies covered in cyanobacterial blooms, raising the potential that BMAA
could get into milk, meat, or vegetables. Dan Dietrich, a toxicology professor at the Universität Konstanz in Germany,
reported finding unspecified large quantities of BMAA in commercially available blue-green algae dietary supplements,
including Spirulina and Aphanizomenon flos-aquae,53 a finding that has not been replicated. Cox isolated BMAA from
desert crusts collected throughout Qatar and suggested that not only might the cyanotoxin have contributed to higher
rates of ALS in Gulf War veterans but also that inhalation of BMAA-containing dust could be a concern elsewhere.54

Drinking water could be a potential exposure route, as well. Lake Houston, which provides drinking water to Houston,
Texas, tested positive for BMAA in the fall of 2011.55 A study of the effectiveness of water treatment techniques on
BMAA removal showed that sand filtration, powdered activated carbon, and chlorination were effective at removing
BMAA-at least at the labora tory scale-with flocculation less so.56 No study has tested the effectiveness of real-world
water treatment methods at BMAA removal, and at the present time, no food or drinking water supplies are tested for
BMAA, although Cox suggests that monitoring would be prudent.16 Researchers at the Institute for EthnoMedicine
recently developed an antibody that detects BMAA, which they imagine being incorporated into a commercial test and a
BMAA-removing water filter.

Epidemiology provides another important line of evidence supporting the BMAA hypothesis. Dartmouth-Hitchcock
Medical Center neurologist Elijah Stommel and colleagues used geographic information system (GIS) software to map
ALS cases and lakes with a history of cyanobacterial blooms in New Hampshire. They found that people living within a
half-mile of cyanobacterially contaminated lakes had a 2.32-times greater risk of developing ALS than the rest of the
population; people around New Hampshire's Lake Mascoma had up to a 25 times greater risk of ALS than the expected
incidence.57 Although BMAA was found in water samples from other lakes, the researchers did not detect it in Lake
Mascoma samples, perhaps, they suggest, because of the small amount of cyanobacteria collected on sampling filters.
Nevertheless, says Stommel, "Our GIS mapping is clearly showing clusters in proximity to [harmful algal blooms]." He
and his team added more patients to their database and are preparing 2 papers for submission in the near future.


Connecting Dots
Scientists around the world continue to research different aspects of the hypothesis. Scientists in Sweden found that
newborn rats treated with BMAA showed early neurotoxicity and impaired learning and memory as adults.58 Others are
investigating high BMAA levels in oysters off the coast of southern France, where an ALS cluster occurs.
In 2010 the National Toxicology Program (NTP) began studies in rat and mouse models to determine, among other
things, whether BMAA accumulates in the brain and other tissues and rates of clearance from those tissues. If
accumulation is demonstrated, mechanistic studies may be designed to further characterize the neurotoxic potential of
BMAA. Preliminary results from the NTP work will be presented at the March 2012 annual meeting of the Society of
Toxicology.

"I don't know if the BMAA hypothesis is true," says Mash. "I know we've measured BMAA in the brain, but proximity is not
causality. You have to have full mechanistic underpinnings [to demonstrate causality], and that's going to take a lot of
money. It's going to take epidemiologic studies. It's going to take other cell culture models to really explain how this
could work. And the big ticket is going to be environmental studies."

Among the most promising development are 2 drugs on the horizon that may help ALS patients. Cox and colleagues
hope to develop a drug to potentially stop BMAA from being misincorporated, and Adeona Pharmaceuticals has begun
Phase II and III clinical trials for a zinc-based drug59 that has already showed promise at slowing ALS progression, albeit
with a very small sample size.60


Since many more people may be exposed to BMAA than succumb to neurodegenerative diseases, Cox suspects that
vulnerability may reflect a gene-environment interaction. If BMAA increases the misfolding of aggregate-prone proteins
such as TDP-43, this could represent such a gene-environment interaction and explain how a single environmental
factor such as BMAA could precipitate ALS-, PD-, and AD-like illness that observed on Guam.
However, no one has yet investigated a genetic basis to BMAA vulnerability. In the meantime, Cox and colleagues
suggest that people should take the threat seriously. "We encourage water managers to take a closer look at
cyanobacterial blooms," he says. "We need to encourage places where there are commercial shellfish fisheries to pay
attention to water quality."

Much work remains to be done. Yet, says Bradley, "I don't think there's any question that the scientific basis of BMAA
and its neurotoxicity is moving along at a very satisfying pace, and it is all concordant with the hypothesis."


References and Notes
      1.      1. Prasad U, Kurland LK. Arrival of new diseases on Guam: lines of evidence suggesting the post-Spanish
origins of ALS and Parkinson's dementia. J Pac Hist 32(2):217-228. 1997. http://www.jstor.org/pss/25169338
    2.      2. Kurland LT, Mulder DW. Epidemiologic investigations of amyotrophic lateral sclerosis. I. Preliminary report
on geographic distribution, with special reference to the Mariana Islands, including clinical and pathologic observations.
Neurology 4(5):355-378. 1954. http://www.ncbi.nlm.nih.gov/pubmed/13185 376
  3.      3. Rao SLN, et al. The isolation and characterization of ?-N-oxalyl-?-?,?-diaminopropionic acid: a neurotoxin
from the seeds of Lathyrus sativus. Biochemistry 3(3):432-436.( 1964. http://dx.doi.org/10.1021/bi00891a022
     4.      4. Bell EA. The discovery of BMAA, and examples of biomagnifications and protein incorporation involving
other non-protein amino acids. Amyotroph Lateral Scler 10: suppl 221-25. 2009.
http://www.ncbi.nlm.nih.gov/pubmed/19929 727
  5.      5. Vega A, Bell EA. ?-Amino-?-methylaminopropionic acid, a new amino acid from seeds of Cycas circinalis.
Phytochemistry 6(5):759-762. 1967. http://dx.doi.org/10.1016/S0031-9422(00) 86018-5
 6.      6. Bell EA, et al. A neurotoxic amino acid in seeds of Cycas circinalis.; In: Toxicity of Cycads: Implications for
Neurodegenerative Diseases and Cancer, Fifth Cycad Conference 1967 (Whiting MG, ed.); New York, NY:Third World
Medical Research Foundation: 1988.
  7.      7. Polsky FI, et al. Distribution and toxicity of ?-amino-?-methylaminopropionic acid. Fed Proc 31(5):1473-1475.
1972. http://www.ncbi.nlm.nih.gov/pubmed/50561 73
    8.      8. Seawright AA, et al. Selective degeneration of cerebellar cortical neurons caused by cycad neurotoxin,
?-?-methylaminoalanine (?-BMAA), in rats. Neuropathol Appl Neurobiol 16(2):153-169. 1990.
http://dx.doi.org/10.1111/j.1365-2990.19 90.tb00944.x
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