The interaction of genetics and environmental toxicants in amyotrophic lateral sclerosis: results from animal models

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in the progressive death of motor neurons, leading to paralysis and eventual death. There is presently no cure for ALS, and only two drugs are available, neither of which provide significant extension of life. The wide variation in onset and progression of the disease, both in sporadic and even in strongly penetrant monogenic familial forms of ALS, indicate that in addition to background genetic variation impacting the disease process, environmental exposures are likely contributors. Epidemiological evidence worldwide implicates exposures to bacterial toxins, heavy metals, pesticides, and trauma as probable environmental factors. Here, we review current advances in gene-environment interactions in ALS animal models. We report our recent discoveries in a zebrafish model of ALS in relation to exposure to the cyanobacterial toxin BMAA, and discuss several results from mouse models that show interactions with exposure to mercury and statin drugs, both leading to acceleration of the disease process. The increasing research into this combinatorial gene-environment process is just starting, but shows early promise to uncover the underlying biochemical pathways that instigate the initial motor neuron defects and lead to their rapidly progressive dysfunction.

Keywords: amyotrophic lateral sclerosis; animal models; gene-environment; genetic susceptibility; risk factors; toxicants.

Figure 1

Influences on the development and progression of amyotrophic lateral sclerosis (ALS). Initiating events may occur through genetic and/or maternal environmental influences immediately after fertilization and throughout fetal development. Multiple insults occur over the lifetime of a person, and these can compound in susceptible motor neurons and surrounding nervous system cells, leading to disease initiation. Additional environmental hits can occur later that impact the progression and eventual fate of the disease process. Motor neurons become stressed and start to develop motor neuron sickness. After many years, compensatory systems are overwhelmed and patients progress into the late pre-clinical stages. Eventually, neurons increasingly fail and ALS becomes both clinically emergent and increasingly progressive. Developing biomarker identifications for preclinical/presymptomatic phases, and understanding the cellular mechanisms underlying the ontology of preclinical gene-environment interactions that lead to initiation and progression of motor neuron sickness may enable the development of preventive, protective, or supportive therapies.