Environmental insults: critical triggers for amyotrophic lateral sclerosis

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases.

Main body: Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies, while environmental insults remain a suspected but largely unexplored source of risk. Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS, but none so far has proved conclusive. We propose a new ALS model which links the current knowledge of genetic factors, ageing and environmental insults. This model provides a mechanism as to how ALS is initiated, with environmental insults playing a critical role.

Conclusion: The available evidence has suggested that inherited defect(s) could cause mitochondrial dysfunction, which would establish the primary susceptibility to ALS. Further study of the underlying mechanism may shed light on ALS pathogenesis. Environmental insults are a critical trigger for ALS, particularly in the aged individuals with other toxicant susceptible genes. The identification of ALS triggers could lead to preventive strategies for those individuals at risk.

Keywords: Amyotrophic lateral sclerosis; Environmental risk factors; Initiation; Mendelian randomisation; Mitochondrial dysfunction; Spread; Trigger.

Fig. 1

Proposed model of ALS pathogenesis. The primary defect is an inherited mitochondrial genetic abnormality, either from the nuclear genome-coded or mitochondrial genes. The mitochondria in the mutation carriers would be in a delicate balance with the struggle to compensate for such a defect. Compensatory capacity diminishes with ageing and the subsequent accumulation of somatic mitochondrial mutations. Environmental insults, particularly in the presence of genetic susceptibilities to toxicants, would further damage the mitochondria and trigger the decompensation process in motor neurons. Any attempt to compensate via excitatory transmission in the surviving neurons would increase their own metabolic load and adversely affect this delicate balance. These ineffective compensatory attempts then initiate a chain reaction of mitochondrial crisis and neuronal apoptosis, leading to ALS

Fig. 2

Genetic proxies for environmental insults, with examples given for poliovirus infection and mercury exposure. This illustrates the Mendelian randomisation approach to infer a causal role of environmental factors in ALS. ALS is associated with the environmental factors via an intermediate status, and the environmental interacting genes (dashed line). But the effect of the interacting genes is directional and facilitates the establishment of the intermediate status. Such an effect can only occur in the presence of environmental insults. The susceptibility alleles of the interacting genes will not be reversely affected by the ALS outcome since all genotypes are determined at conception