L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease

L-β-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 alky...

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Bibliographic Details
Published in:Neurotoxicology (Park Forest South) 2017-03, Vol.59, p.105-109
Main Authors: Potjewyd, G, Day, P J, Shangula, S, Margison, G P, Povey, A C
Format: Article
Language:English
Subjects:
Alanine
Alkylating agents
Alkylating Agents - toxicity
Alkylation
Amino acids
Amino Acids, Diamino - chemistry
Amyotrophic lateral sclerosis
Basal ganglia
Causation
Cell Line, Tumor
Central nervous system diseases
Cytotoxicity
Damage
Dementia disorders
Deoxyribonucleic acid
DNA
DNA Breaks, Single-Stranded - drug effects
DNA damage
DNA Damage - drug effects
Dose-Response Relationship, Drug
Humans
L-Alanine
Movement disorders
Neuroblastoma
Neurodegeneration
Neurological disorders
Neurotoxicity
Nitrates
Nitrosation
Nitrosation - drug effects
Pyridines
Pyridines - toxicity
Sodium
Sodium nitrite
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Summary:L-β-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. 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. 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.
ISSN:0161-813X
1872-9711
DOI:10.1016/j.neuro.2017.01.007