Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder driven by complex interactions among genetic, environmental, developmental, and resilience-related factors. The studies in this Scientific Reports’ Collection highlight major advances across diverse domains that collectively broaden our understanding of ALS pathogenesis. Genetic insights emphasise the need for functional validation, as shown by the non-pathogenic behaviour of the KIF5A P986L variant in Drosophila. Neuroimaging findings reveal hypothalamic atrophy in primary lateral sclerosis, underscoring widespread extra-motor involvement. Epidemiological analyses propose that early-life exposures may form the initial steps in a multistage pathway to ALS, while geographic correlations between ALS and multiple sclerosis suggest shared environmental determinants. Experimental model innovations demonstrate selective muscle preservation in SOD1-G93A mice and introduce electrical impedance myography as a sensitive detection method in zebrafish. Mechanistic work shows that stress influences ALS through PI3K/Akt and focal adhesion pathways, linking environment to cellular vulnerability. Finally, cognitive and brain reserve emerge as important modifiers of disease expression and progression. Together, these studies illustrate ALS as a multisystem, lifespan-spanning disorder shaped by both vulnerability and resilience. Their integration offers a forward-looking framework for advancing biomarker discovery, mechanistic research, and therapeutic development in ALS.
- Ruben J. Cauchi
- Andrew P. Tosolini
