Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

Abstract

The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA) in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS) and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA-induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes.

Keywords: BMAA; excitotoxicity; glutamate receptor; intracellular calcium; neurodegenerative disorders; neuromelanin.

Figure 1

Chemical structure of β-N-methylamino-l-alanine (BMAA) (a), and glutamate (b). From Wikimedia commons.

Figure 2

Molecular aspects of BMAA-induced neurodegeneration mechanisms. At a glutamatergic synapse, BMAA toxin binds to ionotropic (iGluR) and metabotropic (mGluR) receptors. Their activation leads to a significant increase in intracellular Ca²⁺, directly via iGluR and indirectly via mGluR (PLC signaling). This Ca²⁺_i increase promotes ER stress and cell apoptosis. In parallel, inhibition of PP2A induces hyperphosphorylation of Tau protein, which produces tangle degeneration. Finally, the X_c⁻ system is a cystine/glu cotransport that is highjacked by BMAA to penetrate the postsynaptic neuron. Once in the cytoplasm, the toxin is likely to insert into the neosynthesized cellular proteins and to cause the aggregation of misfolded proteins that leads to neuronal death. GRP78: 78 kDa glucose-regulated protein; GSK-3: glycogen synthase kinase-3; iGluR: ionotropic glu receptors; mGluR: metabotropic glu receptors; PLC: phospholipase C; PP2A: protein phosphatase 2A; S1P: sphingosine-1-phosphate; Tau: Tubulin-associated unit; Src: proto-oncogene tyrosine-protein kinase; TDP-43: TAR DNA-binding protein 43.

Figure 3

Origin and functions of melanins in the central nervous system. Melanin accumulates in catecholaminergic neurons and retinal pigmented epithelial cells from catecholamines (dopamine in substantia nigra and noradrenaline in locus ceruleus) and dopa derivates respectively. Intraneuronal neuromelanin could play a protective role during its synthesis by preventing the toxic accumulation of cytosolic catecholamines and derivatives. Those can trigger proteosomal (dopamine and o-quinones) and mitochondrial (o-quinones) dysfunctions, oxidative stress reactions (o-quinones) and α-synuclein oligomerization (o-quinones and 5–6 indolquinol). All those events can ultimately lead to the neuronal death and development of a neurodegenerative process. Melanin polymers limit the accumulation of catecholamines and derivates, therefore fighting neuronal death. In addition, by its ability to scavenge reactive metals, pesticides and other toxins to form stable adducts, this pigment also limits the extent of neurotoxic insults and provide neuroprotection to CNS areas expressing it.

Figure 4

The Janus face of neuromelanin. Metal chelation by neuromelanin occurs throughout life in the CNS. It plays a protective role against iron cation accumulation and noxious consequences of heavy-metal exposure (Cd, Ch, Cu, …). Some pesticides components are known to interact with neuromelanin and finally neurotoxins MPTP and BMAA can bind to this neuronal pigment. Neurodegeneration may occur once burden cannot be fully handled by neuromelanin, letting free highly reactive compounds to accumulate in neuronal cytoplasm, causing neuronal death. Heavily charged melanosomes liberated from dead neurons trigger further inflammatory signals and may also contribute to a neurotoxic environment leading to the dreadful evolution towards neuropathology. There might be a pivotal point beyond which the situation cannot be restored to normal and neuronal survival is jeopardized. This point could be linked to individual neuromelanin stock, type of toxin accumulation, and aging status.