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Review
. 2024 Jun 3;13(11):967.
doi: 10.3390/cells13110967.

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

Marina Hernan-Godoy  1 , Caroline Rouaux  1
Affiliations
Review

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

Marina Hernan-Godoy et al. Cells. .

Abstract

The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.

Keywords: DNA methylation; amyotrophic lateral sclerosis; epigenetics; histone methylation; one-carbon metabolism; therapeutic strategy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Genetic and environmental contributions to ALS. (A). Whether sporadic or familial, ALS arises from the combination of genetic susceptibility and environmental factors. (B). Different models are proposed to explain how genetic and environmental interactions may lead to disease onset. (C). Schematic representations of the molecular cascade leading to cellular toxicity in ALS.
Figure 2
Figure 2
One-carbon metabolism and its impairments in ALS. ALS is associated with alterations of the folate and methionine cycles, such as reported polymorphisms of genes coding for key enzymes (purple), modified levels of metabolites (red), or altered neuronal functions that could indirectly arise from the production of toxic metabolites (orange).
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