Exposure to environmental toxicants and pathogenesis of amyotrophic lateral sclerosis: state of the art and research perspectives

Abstract

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene--environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals--including lead and pesticides-agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research.

Figure 1

Schematic representation of the endogenous neurotoxic reservoir of Beta-N-methylamino-l-alanine (BMAA) that slowly and continuously releases the neurotoxin into cerebral tissue through protein metabolism (Source: Murch et al. [24]).

Figure 2

Aberrant subcellular localization of mutant SOD1 protein and its effect on amyotrophic lateral sclerosis (ALS) pathogenesis: mutant SOD1 interacts with several binding proteins (i.e., endoplasmic reticulum chaperone protein GRP78/Bip, voltage-dependent anion channel 6 or VDCA6, and chromogranin A or ChgA and B or ChgB), resulting in cell death when abnormally redistributed (Source: Ido et al. [4]).

Figure 3

SOD1 structural changes and metal uncoupling in ALS: MBR and WTL-mutant SOD1 (1, 2) may promote metal uncoupling (3), protein aggregation (4, 5), oxidative damage (6) and apoptosis (7) (Source: Rivera-Mancía et al. [137]).

Figure 4

Loss of the normal genetic plasticity with aging: if a gene undergoes environmental-dependent epigenetic change, the ability to respond and revert this modification could be reduced because of aging, and the gene may be repressed (Source: Marques et al. [192]).