β-N-methylamino-L-alanine (BMAA) is a non-proteogenic amino acid which is associated with the onset and progression of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC). BMAA is also implicated in other neurodegenerative diseases and in vitro studies have demonstrated that it is directly harmful to neurons. Despite these strong connections between BMAA and neurodegeneration, its exact role is not clearly understood. One theory suggests that BMAA may inhibit the protein degradation pathway since studies have shown that it can induce changes in the structure of ubiquitin. If ubiquitin is no longer able to degrade unwanted proteins in the brain, this may help to explain the buildup of protein aggregates that is commonly associated with this type of neurodegeneration. For these reasons, the goal of this study was to further assess the ability of BMAA to bind to ubiquitin and potentially alter its structure and function. Computational chemistry programs were used to first simulate the binding of BMAA to wild type ubiquitin protein in order to gain knowledge regarding its predicted binding sites and respective binding affinities. The preliminary results suggest that BMAA preferentially binds near lysine residues, including some which are known to be associated with the formation of polyubiquitin chains. The next step will be to perform circular dichroism experiments using samples of ubiquitin protein mixed with various different concentrations of BMAA in order to determine the extent to which BMAA can alter the secondary structure of ubiquitin. Continuing to perform these types of studies should bring us closer to understanding the mechanisms underlying this type of neurodegeneration.

BMAA-induced neurodegeneration: using computational chemistry to study the underlying mechanisms

ACS Spring 2022

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