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 (Spácil 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.”—Amber Dance

Comments

  1. I believe the line "Green algae, also called cyanobacteria" in this story is erroneous. Cyanobacteria, formerly called "blue algae" or "blue-green algae" are prokaryotes and are completely distinct from green algae, which are eukaryotes. the type of which is Ulva lactuca, an edible common coastal alga. Are the algae "tenuously linked" with Guam ALS/PDC, and those purported to be at the origin of the presence of BMAA in Baltic Sea fauna, bona fide algae or cyanobacteria?

    View all comments by Jean-François Foncin

  2. Reply to comment by Jean-François Foncin
    Dear Dr. Foncin,

    You are quite right. Although cyanobacteria blooms are often called "algal blooms," they are in fact bacteria, not bona fide green algae. Thanks for the catch!

    View all comments by Amber Dance

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References

News Citations

  1. Dietary Toxins and Neurodegenerative Diseases—Guam Revisited
  2. Lou Gehrig’s Disease—On the Rise?
  3. A New Link Between Pesticides and Parkinson's Disease

Paper Citations

  1. Miller G. Neurodegenerative disease. Guam's deadly stalker: on the loose worldwide?. Science. 2006 Jul 28;313(5786):428-31. PubMed.
  2. Cox PA, Sacks OW. Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam. Neurology. 2002 Mar 26;58(6):956-9. PubMed.
  3. Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13380-3. PubMed.
  4. Plato CC, Garruto RM, Galasko D, Craig UK, Plato M, Gamst A, Torres JM, Wiederholt W. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol. 2003 Jan 15;157(2):149-57. PubMed.
  5. Murch SJ, Cox PA, Banack SA. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12228-31. PubMed.
  6. Pablo J, Banack SA, Cox PA, Johnson TE, Papapetropoulos S, Bradley WG, Buck A, Mash DC. Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease. Acta Neurol Scand. 2009 Oct;120(4):216-25. PubMed.
  7. Cox PA, Banack SA, Murch SJ, Rasmussen U, Tien G, Bidigare RR, Metcalf JS, Morrison LF, Codd GA, Bergman B. Diverse taxa of cyanobacteria produce beta-N-methylamino-L-alanine, a neurotoxic amino acid. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5074-8. PubMed.
  8. Montine TJ, Li K, Perl DP, Galasko D. Lack of beta-methylamino-l-alanine in brain from controls, AD, or Chamorros with PDC. Neurology. 2005 Sep 13;65(5):768-9. PubMed.
  10. Fang F, Valdimarsdóttir U, Bellocco R, Ronnevi LO, Sparén P, Fall K, Ye W. Amyotrophic lateral sclerosis in Sweden, 1991-2005. Arch Neurol. 2009 Apr;66(4):515-9. PubMed.
  11. Horner RD, Kamins KG, Feussner JR, Grambow SC, Hoff-Lindquist J, Harati Y, Mitsumoto H, Pascuzzi R, Spencer PS, Tim R, Howard D, Smith TC, Ryan MA, Coffman CJ, Kasarskis EJ. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003 Sep 23;61(6):742-9. PubMed.

External Citations

  1. Cox et al., 2005

Further Reading

Papers

  1. Nelson LM, McGuire V, Longstreth WT, Matkin C. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. Am J Epidemiol. 2000 Jan 15;151(2):156-63. PubMed.
  2. Bradley WG, Banack SA, Cox PA. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2009 Feb 3;72(5):473-4, 476; author reply 475-6. PubMed.
  3. Cox PA. Conclusion to the Symposium: the seven pillars of the cyanobacteria/BMAA hypothesis. Amyotroph Lateral Scler. 2009;10 Suppl 2:124-6. PubMed.
  4. Bradley WG, Cox PA. Beyond Guam: cyanobacteria, BMAA and sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10 Suppl 2:5-6. PubMed.
  5. Steele JC, McGeer PL. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2008 May 20;70(21):1984-90. PubMed.
  6. Kim HJ, Fan X, Gabbi C, Yakimchuk K, Parini P, Warner M, Gustafsson JA. Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2094-9. PubMed.
  7. Cox PA, Richer R, Metcalf JS, Banack SA, Codd GA, Bradley WG. Cyanobacteria and BMAA exposure from desert dust: a possible link to sporadic ALS among Gulf War veterans. Amyotroph Lateral Scler. 2009;10 Suppl 2:109-17. PubMed.
  8. Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP, Galasko D, Lee VM, Trojanowski JQ. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol. 2008 Jan;115(1):133-45. PubMed.

Primary Papers

  1. Stephenson J. The World in Medicine: ALS and Neurotoxin. JAMA. 2010 June 1;303(23):2346.
  2. Jonasson S, Eriksson J, Berntzon L, Spácil 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. PubMed.

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