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.