Next chapter of BMAA detective story

On Thursday morning, Profs Paul Cox and Walter Bradley chaired a session titled ‘Beyond Guam: New Aspects of the BMAA Hypothesis’. This was the latest chapter in a detective story, involving botanists, epidemiologists, clinicians and biochemists that goes back 60 years….

Back in the early 1950s, American doctors started documenting a high incidence of a strange form of MND in the native Chamorro Indian population of the Pacific island of Guam. Those affected exhibited a mix of symptoms covering motor neuron degeneration, dementia and Parkinson’s disease – giving rise to the official name Amyotrophic Lateral Sclerosis-Parkinson-Dementia Complex, or ALS-PDC for short.

Early epidemiology studies linked the disease to a likely environmental exposure with a long-term incubation period, possibly a slow-acting toxin of some type. Subsequent studies linked the disease with the seeds of a member of the cycad family. Cycad seeds formed part of the islanders’ diet and these seeds contain a variety of different chemicals, including some that are toxic to nerve cells. One of these, beta-N-methylamino-L- alanine (BMAA) was a prime suspect.

But cycad seeds don’t make BMAA themselves – it is actually made by a form of cyanobacteria (blue-green algae) that live in the roots of the cycad plants. The BMAA toxin is then concentrated in the plant seeds, which were ground up as flour to make a form of bread.

In the lab, it could be shown that BMAA readily killed nerve cells, did so at concentrations that were much higher than those that would be found in the cycad bread. This led the epidemiologists to ask the question ‘What else eats cycad seeds?’ The answer was flying foxes – a type of fruit eating bat – and flying foxes in turn are considered a delicacy by the locals…

As Prof Cox explained in his introductory overview to the delegates, we have a very nice example of biomagnification. BMAA is made by algae, is concentrated in cycad seeds, is further concentrated in the bats and is finally eaten by the locals, where it presumably builds up in brain tissue over time.

This theory isn’t universally supported by researchers – for example, if a genetic factor was involved, it would likely be more prevalent in an isolated, island population such as Guam. However, the epidemiologists like to point out that the bat population has plummeted over the past 40 years (perhaps due to increased use of guns by the islanders or the introduction of an invasive tree-climbing snake) as has the incidence of ALS-PDC!

Of course, cyanobacteria are found all over the world, so it begs the question of whether BMAA might be present in very low levels in other places, perhaps acting as a subtle factor that predisposes people across the world to develop MND? Certainly, BMAA has been found to be present in water sources in various locations, in particular marine environments where, as explained by Dr Estelle Masseret (University of Montpellier) it can be further concentrated in shellfish. It has also been shown to be present in the brains of people with neurodegenerative diseases who have never been within a thousand miles of Guam.

Cyanobacteria - Dr Paul Cox

The levels of ‘free’ BMAA in the brain are relatively low, so a theory has emerged in recent years that most of the BMAA in the brain tissue is ‘protein-bound’ – not sticking randomly to proteins, but actually being unwittingly incorporated into the protein structure during the manufacturing process. This isn’t surprising, since BMAA is an amino acid and amino acids are the building blocks of every protein in our body.

The difference with BMAA is that it is an ‘unnatural’ amino acid. By this I mean that proteins are normally made from a combination of 20 amino acids. BMAA isn’t one of them, so when it gets incorporated, it can subtly alter the structure of the protein. And when protein structure is altered in neurons, it invariably leads to the aggregation of proteins, one of the classic pathological hallmarks of neurodegenerative diseases. Since our neurons have to last a lifetime, an accumulation of BMAA and misfolded proteins over many years could make neurons more susceptible to damage.

One big unanswered question is which amino acids is BMAA being mistaken for? Through some elegant experiments, Prof Ken Rogers (University of Technology, Sydney) showed  that part of the protein making ‘machinery’ is specifically mistaking BMAA for serine, the amino acid that is structurally the most similar. The ‘machinery’ is question is an enzyme called tRNA synthetase and Prof Rogers pointed out that if this process is inhibited in mice, the neurons are the first to start to show damage, indicating that they are particularly vulnerable if tRNA synthetase is not doing its job correctly.

It does raise the question of whether BMAA is incorporated more into proteins that contain the largest proportion of serine amino acids. That question has not yet been addressed, but it is interesting that the protein TDP-43, which is known to misfunction in up to 90% of cases of MND, is a protein that is made up of an unusually high number of serine amino acids,

As with many aspects of biomedical research, this session raised more questions than answers, but the really encouraging fact was that the questions were coming from scientists outside the immediate BMAA field. It will take additional expertise to definitively demonstrate whether or not BMAA is indeed a common risk factor that might prime people to develop neurodegenerative disease later in life. This session, together with a follow-up workshop organised for the end of the day, will throw up the key next steps in this field of investigation – how to strengthen the evidence in cell and animal models, how to improve the analytical methods and how to collaborate more closely together in the future, drawing in new expertise from across the world of neuroscience.

Read our official press release on day two of the symposium.

4 thoughts on “Next chapter of BMAA detective story

  1. Pingback: Round up of news from the 22nd International Symposium on ALS/MND « MND Research

  2. Pingback: Researchers in Australia identify how blue-green algae may cause some cases of MND | MND Research

  3. Hi all just been reading about the blue green algae and possible link to MND…I would like to ask …is it possible for this algae or other algae to live in domestic hot water cylinders?

    • Dear Pat,

      In response to your question about whether it is possible for algae to live in domestic hot water cylinders, the short answer is that it is highly unlikely for any type of algae to live in this environment.

      This is because algae need to take in sunlight in order for them to make their own energy by a process known as ‘photosynthesis’. Domestic hot water cylinders are not exposed to light, and due to this algae would not be able to survive in this environment. Hot water cylinders are also kept at high temperatures which would hopefully be too hot for any type of algae to survive.

      I hope this answers your question and if you have any further questions about MND research please do not hesitate to contact us on 01604 611 880 or via research@mndassociation.org.

      Kind regards,
      Samantha Price, PhD
      Research Information Co-ordinator
      Research Development team, MND Association, UK

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