L-BMAA Induced ER Stress and Enhanced Caspase 12 Cleavage at Low Nonexcitotoxic Concentrations

One of the great challenges of scientific investigation is determining genuine cause and effect. Often times, one thing can appear to be causing another, but can easily be confused for correlation. Determining the true causal mechanisms behind a scientific phenomenon, particularly the epidemiology of diseases, is essential to understanding how they work and how they can be dealt with. A good example of this is the abnormally high incidence of Amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in the native Chamorro population on Guam Island. Previous studies have linked the increased frequency of this disease in this geographic region to an increased exposure to β-N-methylamino-L-alanine (L-BMAA), a cyanobacterial neurotoxin. This causal link has been empirically confirmed several times, but L-BMAA excitotoxicity is usually only found in instances where concentrations of L-MBAA are very high -much higher than what the Chamorro population in Guam would have been exposed to. As such, Okle et al. from the University of Konstanz in Germany set out to determine if L-BMAA could play a role in the onset of ALS/PDC even if found in low concentrations.

To do this, Okle and the team decided to look at the role of L-BMAA in inducing misfolded and oxidized proteins, given that this is a hallmark of neurodegenerative disorders such as ALS/PDC. By measuring the effects of low concentrations of L-BMAA on mechanisms such as protein oxidation and ubiquitination, 20S proteasomal and capase 12 activity, expression of the ER stress marker CHOP, and the phosphorylation of elf2α, the research team could determine the role L-BMAA plays in the onset of ALS/PDC. One of the ways they carried out these measurements was by using the Amplite Fluorimetric Proteasome 20S Activity Assay Kit . This kit uses LLVY-R110 as a fluorogenic indicator for proteasome activity, and when cleaved, produces a bright fluorescent glow, allowing researchers to obtain robust and reliable results.

At the conclusion of their study, Okle et al. found an increase or enhancement of each of the above activities, indicating that low concentrations of L-BMAA can in fact lead to misfolded proteins and ER stress, suggesting a causal link with neurodegenerative disorders. By looking at the specific case in Guam, these researchers were able to make a relatively significant breakthrough in understanding the pathology of ALS-PDC. A previously assumed causality was determined to be a misunderstood correlation, and by providing more nuance to the understanding of this process, researchers will be able to move forward more confidently in the search for a cure. Studies like this could not be carried out unless the tools being used can be trusted to deliver accurate results. The Amplite Fluorimetric Proteasome 20S Activity Assay Kit is highly adaptable and has been repeatedly tested to assure quality and accuracy. Armed with the results from a study such as this one, researchers can advance forward towards a world without these neurodegenerative disorders.

References

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1. Okle, Oliver, et al. "L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations." toxicological sciences 131.1 (2012): 217-224.