Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin.

While rising global rates of neurodegenerative disease encourage early diagnosis and therapeutic intervention to block clinical expression (secondary prevention), a more powerful approach is to identify and remove environmental factors that trigger long-latencybrain disease (primary prevention) by acting on a susceptible genotype or acting alone. The latter is illustrated by the post-World War II decline and disappearance of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC), a prototypical often-familial neurodegenerative disease formerly present in very high incidence on the island of Guam. Lessons learned from 75 years of investigation on the etiology of ALS/PDC include: the importance of focusing field research on the disease epicenter and patients with early-onset disease; soliciting exposure history from patients, family, and community to guide multidisciplinary biomedical investigation; recognition that disease phenotype may vary with exposure history, and that familial brain disease may have a primarily environmental origin.

Genomic insights into the biosynthesis and physiology of the cyanobacterial neurotoxin 3-N-methyl-2,3-diaminopropanoic acid (BMAA).

Cyanobacteria are an ancient clade of photosynthetic prokaryotes, present in many habitats throughout the world, including water resources. They can present health hazards to humans and animals due to the production of a wide range of toxins (cyanotoxins), including the diaminoacid neurotoxin, 3-N-methyl-2,3-diaminopropanoic acid (β-N-methylaminoalanine, BMAA). Knowledge of the biosynthetic pathway for BMAA, and its role in cyanobacteria, is lacking.

Genomic insights into the biosynthesis and physiology of the cyanobacterial neurotoxin 2,4-diaminobutanoic acid (2,4-DAB).

Cyanobacteria are an ancient clade of photosynthetic prokaryotes, whose worldwide occurrence, especially in water, presents health hazards to humans and animals due to the production of a range of toxins (cyanotoxins). These include the sometimes co-occurring, non-encoded diaminoacid neurotoxins 2,4-diaminobutanoic acid (2,4-DAB) and its structural analogue β-N-methylaminoalanine (BMAA). Knowledge of the biosynthetic pathway for 2,4-DAB, and its role in cyanobacteria, is lacking.

Environmental distribution of the neurotoxin l-BMAA in species.

The environmental distribution of the neurotoxic amino acid, 3--methyl-2,3-diaminopropanoic acid (BMAA), first isolated in 1967, was initially believed to be limited to tropical and subtropical plants of the genus The seeds of one such species, which had been used historically on the Pacific island of Guam as a foodstuff, had a reputation for neurotoxicity. Some 40 years later the amino acid was detected in terrestrial and aquatic cyanobacteria and in other aquatic organisms. Overlooked was the discovery of BMAA in peptides of bizarre structure that had been isolated in 1975 from during a search for antibiotics.

50 years of research on α-amino-β-methylaminopropionic acid (β-methylaminoalanine).

The isolation of α-amino-β-methylaminopropionic acid from seeds of Cycas circinalis (now C. micronesica Hill) resulted from a purposeful attempt to establish the cause of the profound neurological disease, amyotrophic lateral sclerosis/parkinsonism/dementia, that existed in high frequency amongst the inhabitants of the western Pacific island of Guam (Guam ALS/PD). In the 50 years since its discovery the amino acid has been a stimulus, and sometimes a subject of mockery, for generations of scientists in a remarkably diverse range of subject areas.

Metabolic solutions to the biosynthesis of some diaminomonocarboxylic acids in nature: Formation in cyanobacteria of the neurotoxins 3-N-methyl-2,3-diaminopropanoic acid (BMAA) and 2,4-diaminobutanoic acid (2,4-DAB).

The non-encoded diaminomonocarboxylic acids, 3-N-methyl-2,3-diaminopropanoic acid (syn: α-amino-β-methylaminopropionic acid, MeDAP; β-N-methylaminoalanine, BMAA) and 2,4-diaminobutanoic acid (2,4-DAB), are distributed widely in cyanobacterial species in free and bound forms. Both amino acids are neurotoxic in whole animal and cell-based bioassays. The biosynthetic pathway to 2,4-DAB is well documented in bacteria and in one higher plant species, but has not been confirmed in cyanobacteria.

Analysis of BMAA enantiomers in cycads, cyanobacteria, and mammals: in vivo formation and toxicity of D-BMAA.

Chronic dietary exposure to the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) triggers neuropathology in non-human primates, providing support for the theory that BMAA causes a fatal neurodegenerative illness among the indigenous Chamorro people of Guam. However, since there are two stereoisomers of BMAA, it is important to know if both can occur in nature, and if so, what role they might play in disease causation. As a first step, we analysed both BMAA enantiomers in cyanobacteria, cycads, and in mammals orally dosed with L-BMAA, to determine if enantiomeric changes could occur in vivo.

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor.

There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations.

Brain glutathione as a target for aetiological factors in neurolathyrism and konzo.

Both neurolathyrism and konzo are associated with the nutritional dependence of human populations on a single plant food. These diseases express themselves as chronic disorders of upper motor neurones, leading to signs and symptoms that characterise amyotrophic lateral sclerosis (motor neurone disease). The plant food associated with neurolathyrism is grass pea, which contains the neurotoxic β-N-oxalyl-α,β-diaminopropionic acid (β-ODAP).

Toxicity of non-protein amino acids to humans and domestic animals.

Non-protein amino acids are common in plants and are present in widely consumed animal feeds and human foods such as alfalfa (Medicago sativa), which contains canavanine, and lentil (Lens culinaris), which contains homoarginine. Some occur in wild species that are inadvertently harvested with crop species. Some non-protein amino acids and metabolites can be toxic to humans, e.

Three phases of research on beta-N-methylamino-L-alanine (BMAA)--a neurotoxic amino acid.

This paper discusses various aspects of the research that lead from the discovery of beta-N-methylamino-L-alanine (BMAA) to consider a variety of mechanisms that might explain the acute and chronic toxicities of this non-protein amino acid. Such is the fashion of science that current work represents the third phase of research on this compound over a period of more than 40 years. BMAA is now known to exist not only in the plant genus Cycas, where it is synthesized by symbiotic cyanobacteria in the coralloid roots of the plants, but to be widely distributed in the many sites at which free living cyanobacteria abound.

Beta-N-methylaminoalanine (BMAA): metabolism and metabolic effects in model systems and in neural and other tissues of the rat in vitro.

The non-protein amino acid, beta-N-methylaminoalanine (BMAA), is neurotoxic and has been implicated in the amyotrophic lateral sclerosis-Parkinsonism-dementia (ALS-PD) complex of Guam. This concept remains controversial, in part because of the lack of a convincing animal model. The neuropharmacology of BMAA is well established, but little is known of its metabolism.

The Lathyrus excitotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid is a substrate of the L-cystine/L-glutamate exchanger system xc-.

Beta-N-oxalyl-L-alpha-beta-diaminopropionic acid (beta-L-ODAP) is an unusual amino acid present in seeds of plants from the Lathyrus genus that is generally accepted as the causative agent underlying the motor neuron degeneration and spastic paraparesis in human neurolathyrism. Much of the neuropathology produced by beta-L-ODAP appears to be a direct consequence of its structural similarities to the excitatory neurotransmitter L-glutamate and its ability to induce excitotoxicity as an agonist of non-NMDA receptors. Its actions within the CNS are, however, not limited to non-NMDA receptors, raising the likely possibility that the anatomical and cellular specificity of the neuronal damage observed in neurolathyrism may result from the cumulative activity of beta-L-ODAP at multiple sites.