Fig. 1.

The seeds for the development of amyotrophic lateral sclerosis (ALS) may be sown shortly after conception. Motor neurons and supporting glia are susceptible to many potential insults, such as neuroinflammation, excitotoxicity, mitochondrial dysfunction, excessive oxidative stress and environmental risk factors. Epigenetic influences may further determine individual sensitivity and susceptibility. Environmental risk factors continue to exert their influence throughout life. In combination, these factors cause protein dysfunction and aggregation. Motor neurons and surrounding astrocytes are metabolically stressed, progressively losing function (MN ‘sickness’). After years or decades, cytosolic compensatory mechanisms begin to fail and a clinically identifiable pre-symptomatic stage starts in which electrophysiological and imaging abnormalities become detectable at a macroscopic level. Finally, the motor system fails, and ALS becomes symptomatic and relentlessly progressive (Eisen et al., 2014).