Work

The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study

Year: 2025

Type: article

Abstract: Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β- N -methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l -serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l -serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l -serine biosynthesis pathway and broad disturbances in energy metabolism. • Human exposure to cyanobacterial toxins is linked to clusters of sporadic ALS worldwide. • Proteomic analysis of cells exposed the cyanotoxins β- N -methylamino-L-alanine (BMAA) and L-2,4-diaminobutyric acid (2,4 DAB) revealed significant changes in the l -serine biosynthesis pathway (SBP) and pathways associated with cellular energy production. • Co-incubation of cells with l -serine restored expression levels of PHGDH, the first committed step in serine biosynthesis as did pre-treatment of cells with the glycolytic product pyruvate. • This is the first study to link BMAA and 2,4-DAB to impairment in the SBP and broad disturbances in energy metabolism.

Source: Toxicology in Vitro

DOI: 10.1016/j.tiv.2025.106058

Authors: Lisa Pu, Joel R. Steele, Connor R. Phillips, Jake P. Violi, Kenneth J. Rodgers

Institutions: University of Technology Sydney, Monash University, UNSW Sydney

Language: English

Topic: Aquatic Ecosystems and Phytoplankton Dynamics

Subfield: Environmental Chemistry

Field: Environmental Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,200