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Review
. 2017 Jun;4(2):200-207.
doi: 10.1007/s40572-017-0144-1.

Evaluating a Gene-Environment Interaction in Amyotrophic Lateral Sclerosis: Methylmercury Exposure and Mutated SOD1

Jordan M Bailey  1   2 , Alexandra Colón-Rodríguez  1   2   3 , William D Atchison  4   5   6   7
Affiliations
Review

Evaluating a Gene-Environment Interaction in Amyotrophic Lateral Sclerosis: Methylmercury Exposure and Mutated SOD1

Jordan M Bailey et al. Curr Environ Health Rep. 2017 Jun.

Abstract

Purpose of review: Gene-environment (GxE) interactions likely contribute to numerous diseases, but are often difficult to model in the laboratory. Such interactions have been widely hypothesized for amyotrophic lateral sclerosis (ALS); recent controlled laboratory studies are discussed here and hypotheses related to possible mechanisms of action are offered. Using methylmercury exposure and mutated SOD1 to model the impacts of such an interaction, we interpret evidence about their respective mechanisms of toxicity to interrogate the possibility of additive (or synergistic) effects when combined.

Recent findings: Recent work has converged on mechanisms of calcium-mediated glutamate excitotoxicity as a likely contributor in one model of a gene-environment interaction affecting the onset and progression of ALS-like phenotype. The current experimental literature on mechanisms of metal-induced neuronal injury and their relevant interactions with genetic contributions in ALS is sparse, but we describe those studies here and offer several integrative hypotheses about the likely mechanisms involved.

Keywords: AMPA receptor; Amyotrophic lateral sclerosis; Calcium homeostasis; Gene-environment (GxE) interaction; Glutamate; Methylmercury.

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Conflict of interest statement

Conflict of Interest

Jordan M. Bailey, Alexandra Colón-Rodríguez, and William D. Atchison declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Role of AMPA receptors in ALS and MeHg toxicity on MNs. In ALS, AMPA receptors contribute to the alterations in intracellular Ca2+. This effect is in part due to the decrease in RNA editing of the GluA2, which results from a decrease in ADAR2. That contributes the increase in the unedited form of GluA2 (GluA2Q) containing receptors in MNs. This is one of the mechanisms that contribute to MN cell death in ALS. MeHg-induced Ca2+ dysregulation in MNs is also mediated in part by Ca2+ permeable AMPA receptors. Our preliminary studies have shown that there is a decrease of ADAR2. However, we do not know how and if the GluA2 subunit is affected by MeHg exposure. This should be the focus of future studies.
See this image and copyright information in PMC

References

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