Potential Guamian ALS Toxin Also Scourge of the Baltic Sea

Toxic marine algae can cause oceanic dead zones, suffocation in fish, insanity in marine mammals—and perhaps, according to a recent PNAS study, neurodegenerative disease. Researchers from Stockholm University in Sweden reported in the May 18 issue that a toxic amino acid called β-methylamino-L-alanine (BMAA)—best known for a tenuous connection to neurological disease in Guam—is produced by algae in the Baltic Sea, and accumulates in many of the fish we like to call dinner. More recently, the study received attention in the June 16 JAMA’s The World in Medicine feature. The discovery, the PNAS authors write, is alarming and requires attention.

For decades, scientists have struggled to understand the odd syndrome experienced by many of the Chamorro people in Guam (see Miller, 2006). Their disease features characteristics of amyotrophic lateral sclerosis as well as a Parkinson-dementia complex, and is called ALS/PDC. Over the years, scientists led by ethnobotanist Paul Cox have pointed the finger of blame at fruit bats the Chamorro regularly consume, the cycad seeds that the bats (and people) eat, and green algae in the cycad’s roots (Cox and Sacks, 2002; also see ARF related news story on Cox et al., 2003).

Incidence rates have declined over time (Plato et al., 2003), as has the bat population; the Chamorro now feed their fruit bat craving with animals imported from cycad-free islands. Some scientists think BMAA, produced by the algae and reaching dinner plates via cycad flour or bats boiled in coconut milk, a local delicacy, accumulates in the body’s proteins and causes toxicity with its slow release (Murch et al., 2004). The toxin could accumulate as it moves up the food chain to people. Studies with human brain tissue have even hinted that BMAA may accumulate in the brains of people with Alzheimer disease or ALS who have never lived on Guam, suggesting it might be a common factor in neurodegenerative disease (Pablo et al., 2009).

However, many scientists are skeptical of the theory. BMAA is far from proven to have any role in Guam ALS/PDC, wrote John Trojanowski, of the University of Pennsylvania, in an e-mail to ARF.

Green algae, also called cyanobacteria, are present worldwide, and the majority of species, it is thought, produce BMAA (Cox et al., 2005). The Swedish researchers wondered—and worried—that the BMAA might show up in other parts of the globe. Led by first author Sara Jonasson and senior author Birgitta Bergman, they dredged the Baltic for samples of algae, fish, and mollusks, then tested their samples for BMAA.

The methods by which scientists detect BMAA are part of the controversy over the molecule. BMAA is small, hydrophilic, and has no useful chromophores or fluorophores to help scientists quantify it. It is present in small quantities, and a structural isomer that produces false positives can further hamper its detection. While Cox and colleagues find it in brain tissue, for example, others do not, and argue that preservation methods may create molecules that mimic BMAA (Montine et al., 2005). The Cox team responds that researchers must be careful to use optimized high-pressure liquid chromatography (HPLC) protocols to discover BMAA (Cox et al., 2005).

In the current study, the authors used a recent technique, combining HPLC with tandem mass spectrometry to detect BMAA (Spcil et al., 2010). This method separates BMAA from its isomer and can detect the rogue amino acid at levels as low as 70 femtomoles (about 42 billion particles). This seems to be a good assay for BMAA, said Douglas Galasko of the University of California, San Diego, who was not involved in the study. However, he was skeptical that it measures BMAA that is naturally free and available in a physiological system. To extract BMAA, the authors hydrolyzed their samples in six molar hydrochloric acid at a temperature of 110 degrees Celsius—pretty extreme conditions not found in the body. If BMAA is so tightly bound within proteins, Galasko wondered, Is this then a pool of BMAA that can cause disease

According to the PNAS analysis, the cyanobacteria that regularly bloom in the Baltic Sea had the toxin, and it accumulated in organisms further up the food chain. Zooplankton, which feed on cyanobacteria, carried a sixfold higher concentration. The catch of the day had it too, from herring and whitefish to mussels and oysters. Fish concentrations varied considerably, from none to 200 times that in cyanobacteria. BMAA was higher in fish brains than in muscle—good news for seafood lovers as long as you don’t like to eat the brains.

The occurrence and bioaccumulation of BMAA in a temperate ecosystem outside Guam suggests that BMAA may be a globally widespread toxin that represents a potential threat to human health, the authors concluded. Algal blooms are on the rise, they note, and some research suggests ALS rates have increased in Sweden as well (see ARF related news story on Fang et al., 2009). They suggest it is urgent to look for BMAA in additional fish, and study how it moves in food webs.

Other research has pointed to environmental factors as a cause in neurodegenerative disease. For example, some think Gulf War veterans were exposed to toxins, explaining their unusually high rate of ALS (Horner et al., 2003). And pesticide exposure might bear some of the blame for Parkinson disease (see ARF related news story). Whether BMAA-laced algal blooms are at all responsible for motor neuron disease in people is far from proven, however. I am disappointed that this paper did not link the presence of BMAA in Baltic Sea aquatic life with an increased prevalence of disease in populations that rim the Baltic Sea, Trojanowski noted.

Galasko said it makes sense that BMAA bioaccumulates. There could, in theory, be ubiquitous exposure to something like cyanobacteria or BMAA, he said. The question is, Is it bad for you—or anybody, or anything And their paper does not begin to address that.

Jonasson S, Eriksson J, Berntzon L, Spcil Z, Ilag LL, Ronnevi LO, Rasmussen U, Bergman B. Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9252-7. Abstract

Stephenson J. The World in Medicine: ALS and Neurotoxins. JAMA. 2010 Jun 16;303(23):2346.

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