The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation

Abstract

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 tRNAAla 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.

Glyphosate pathways to modern diseases VI: Prions, amyloidoses and autoimmune neurological diseases

“…The toxicity of these products may be due to the fact that they replace coding analogues during protein synthesis. Examples include: azetidine-2-carboxylic acid (Aze), a proline analogue [37,38]; glufosinate, a glutamate analogue that is also a popular herbicide [39]; β-N-methylamino-L-alanine (BMAA), an analogue of serine [40]; and L-canavanine, a natural analogue of L-arginine that is exploited as an insecticide [41,42]. A remarkable true-life story involving a 119-day Alaskan wilderness experiment conducted by Christopher McCandless was recounted in the book Into the Wild by Jon Krakauer (later made into a popular movie) [43].…”

The neurotoxin BMAA in aquatic systems : analysis, occurrence and effects

“…And although precipitated bound BMAA is often referred to as "protein-associated" BMAA, the exact nature of the association of BMAA with proteins in natural tissues also needs to be elucidated. In vitro, BMAA can be incorporated into 1 proteins [65,90], but in vivo experiments with bacteria do not show protein incorporation [91]. Whether protein incorporation also occurs in vivo is therefore still to be determined.…”

“…[61][62][63][64]). Furthermore, there is some indication that BMAA incorporation leads to protein misfolding in vitro [65], but this area needs further research. But even though it is established that BMAA is a neurotoxin, an animal model for BMAA-induced neurodegenerative diseases is still lacking [60,66].…”

“…It was suggested that this latency period was caused by the presence of a 'toxic reservoir', in which BMAA was stored in a protein-associated form and was slowly released in its free form [70]. Recent studies indeed indicate that BMAA can either associate with, or be incorporated into proteins [65,90,141,176], although this association might in some cases be superficial [91]. BMAA can be maternally transferred as shown for mice, either directly [177] or trough milk during lactation [178].…”

“…This fraction is commonly referred to as "protein associated" or "protein bound" [33,35], but the association of BMAA with proteins in natural samples still needs to be elucidated. In vitro, BMAA can be incorporated into proteins and can be associated to proteins through non-covalent bonding [65,90], but in vivo experiments with bacteria do not show protein incorporation [91]. Only few studies look at soluble bound BMAA in an isolated fraction (e.g., [89,92,103,198]).…”