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 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.
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Amyotrophic lateral sclerosis
Sporadic amyotrophic lateral sclerosis
Familial amyotrophic lateral sclerosis
Superoxide dismutase 1
Fused in sarcoma/translocated in sarcoma
TAR DNA-binding protein 43
Chromosome 9 open reading frame 72
Coproporphyrinogen oxidase 4
Brain-derived neurotrophic factor
Single nucleotide polymorphisms
- [Ca2+]i :
Internal calcium concentration
Reactive oxygen species
Excitatory amino acid transporter
1-Naphthyl acetyl spermine
AMPA receptor subunit 2
Adenosine deaminase acting on RNA
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Supported by grants NIEHS T32 ES00725527 (Jordan M. Bailey, Alexandra Colón-Rodríguez) and NIH Grant R01 ES024064 (Jordan M. Bailey, Alexandra Colón-Rodríguez, William D. Atchison).
Conflict of Interest
Jordan M. Bailey, Alexandra Colón-Rodríguez, and William D. Atchison declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
All reported studies/experiments with animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
This article is part of the Topical Collection on Mechanisms of Toxicity
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Bailey, J.M., Colón-Rodríguez, A. & Atchison, W.D. Evaluating a Gene-Environment Interaction in Amyotrophic Lateral Sclerosis: Methylmercury Exposure and Mutated SOD1. Curr Envir Health Rpt 4, 200–207 (2017). https://doi.org/10.1007/s40572-017-0144-1
- Amyotrophic lateral sclerosis
- Gene-environment (GxE) interaction
- AMPA receptor
- Calcium homeostasis