LAUSR

Background: L‐&bgr;‐N‐methylamino‐L‐alanine (BMAA) is a non‐proteinic amino acid, that is neurotoxic in vitro and in animals, and is implicated in the causation of amyotrophic lateral sclerosis and parkinsonism‐dementia complex (ALS‐PDC) on Guam. Given that natural amino acids can be N‐nitrosated to form toxic alkylating agents and the structural similarity of BMAA to other amino acids, our hypothesis was that N‐nitrosation of BMAA might result in a toxic alkylating agent, providing a novel mechanistic hypothesis for BMAA action. Findings: We have chemically nitrosated BMAA with sodium nitrite to produce nitrosated BMAA (N‐BMAA) which was shown to react with the alkyl‐trapping agent, 4‐(p‐nitrobenzyl)pyridine, cause DNA strand breaks in vitro and was toxic to the human neuroblastoma cell line SH‐SY5Y under conditions in which BMAA itself was minimally toxic. Conclusions: Our results indicate that N‐BMAA is an alkylating agent and toxin suggesting a plausible and previously unrecognised mechanism for the neurotoxic effects of BMAA. HighlightsA novel mechanism of L‐&bgr;‐N methylamino‐L‐alanine BMAA toxicity is proposed.N‐Nitrosation of BMAA results in an alkylating agent that causes DNA strand breaks.Nitrosated BMAA is toxic to the human neuroblastoma cell line SH‐SY5Y.Endogenous nitrosation of BMAA may help to cause neurodegenerative disease.