The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation

• Published in: PloS one Vol. 8; no. 9; p. e75376
• Main Authors: Dunlop, Rachael Anne, Cox, Paul Alan, Banack, Sandra Anne, Rodgers, Kenneth John
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25-09-2013; Public Library of Science (PLoS)
• Subjects: Acids; Agglomeration; Alanine; Alzheimer's disease; Amino acids; Amino Acids, Diamino - analysis; Amino Acids, Diamino - metabolism; Amyotrophic lateral sclerosis; Apoptosis; Ataxia; Cell culture; Cell Culture Techniques; Cell Line; Cerebellum; Chromatography, High Pressure Liquid; Cyanobacteria; Cyanobacteria - chemistry; Dementia disorders; Disease; Disease control; Environmental factors; Ethnomedicine; Glutamic acid; Human Umbilical Vein Endothelial Cells; Humans; L-Alanine; L-Lactate Dehydrogenase - metabolism; L-Serine; Laboratory animals; Laboratory tests; Lewy bodies; Movement disorders; Mutation; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - chemistry; Neuroblastoma; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurosciences; Paralysis; Parkinson's disease; Penicillin; Polypeptides; Progressive supranuclear palsy; Protein folding; Protein interaction; Protein synthesis; Proteins; Proteostasis Deficiencies - genetics; Public health; Tandem Mass Spectrometry; Tau protein; Toxicology; Tritium; Wyoming; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075376

Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNA(Ala) with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of L-serine into human proteins. We also report that this misincorporation can be inhibited by L-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS.