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

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.

Summary

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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Fig. 1

Abbreviations

GxE:

Gene-environment interaction

ALS:

Amyotrophic lateral sclerosis

sALS:

Sporadic amyotrophic lateral sclerosis

fALS:

Familial amyotrophic lateral sclerosis

SOD1:

Superoxide dismutase 1

FUS:

Fused in sarcoma/translocated in sarcoma

TDP-43:

TAR DNA-binding protein 43

C9orf72:

Chromosome 9 open reading frame 72

MN:

Motor neuron

CPOX4:

Coproporphyrinogen oxidase 4

BDNF:

Brain-derived neurotrophic factor

MeHg:

Methylmercury

SNP:

Single nucleotide polymorphisms

Glu:

Glutamate

[Ca2+]i :

Internal calcium concentration

NMDA:

N-methyl-D-aspartate

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ROS:

Reactive oxygen species

EAAT:

Excitatory amino acid transporter

CNQX:

6-Cyano-7-nitroquinoxaline-2,3-dione

NAS:

1-Naphthyl acetyl spermine

GluA2:

AMPA receptor subunit 2

ADAR2:

Adenosine deaminase acting on RNA

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Acknowledgements

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).

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Correspondence to William D. Atchison.

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

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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).

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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

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Keywords

  • Amyotrophic lateral sclerosis
  • Gene-environment (GxE) interaction
  • Methylmercury
  • AMPA receptor
  • Glutamate
  • Calcium homeostasis