Exposure to cyanobacteria and BMAA in ALS through the gut environment microbiome

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DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is characterized by motor neuron-specific degeneration leading to a progressive and lethal paralysis. Up to 10% of all ALS cases are characterized by a family history of the disease with the remaining 90% of the patients suffering from sporadic ALS. For both patient groups, familial and sporadic ALS, a gene-environment interaction is hypothesized, but barely any environmental risk factors have been identified. It has been postulated in a specific population on the island Guam with high incidence of ALS that the disease is caused by neurotoxin accumulation through the consumption of the cycad nuts and biomagnification of such. This neurotoxin is �-N-Methylamino-L-alanine (BMAA) and is associated to ALS symptoms. Furthermore increased levels of BMAA are reported in post mortem brain tissue of ALS patients. However, these studies have been small and a more systematic approach is needed to decipher the role of BMAA in ALS susceptibility and disease progression. BMAA is produced by cyanobacteria and this bacteria has been associated to localized 'outbreaks' of ALS in the past, including in the USA. Cyanobacteria, also known as blue-green algae, have recently been found to also reside in the human gut microbiome. In this explorative study, we hypothesize that exposure to cyanobacteria in the gut of ALS patients in the United States is an environmental risk factor contributing to ALS by producing the neurotoxin BMAA. Alternatively, other species in the human gut microbiome may play a role in the disease. We will examine BMAA levels in post mortem spinal cord tissues of ALS patients and unaffected control subjects. Furthermore, we will collect biosamples of 30 ALS patients and 30 unrelated control subjects to assess BMAA levels in blood, saliva and fecal samples. We will perform whole metagenome shotgun sequencing of the gut microbiome to study the presence of (different strains of) cyanobacteria in patients and controls. The gut microbiome profiles will also be used in an unbiased analysis to explore differences that may be related to disease. This study will be one of the first to systematically examine the environmental exposure of cyanobacteria and its neurotoxins in human ALS.