Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies

•The pathophysiological mechanisms underlying amyotrophic lateral sclerosis (ALS) are multifactorial.•Genetic factors and dysfunction of vital molecular pathways underlie ALS pathogenesis.•Novel therapeutic approaches have been developed in ALS.

Amyotrophic lateral sclerosis (ALS) is the most frequently occurring of the neuromuscular degenerative disorders, with a median survival time of 3–5 years. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. To date 16 genes and loci have been associated with ALS, with mutations in DNA/RNA-regulating genes including the recently described c9orf72 (chromosome 9 open reading frame 72) gene, suggesting an important role for dysregulation of RNA metabolism in ALS pathogenesis. Further, dysfunction of molecular pathways, including glutamate-mediated excitotoxicity, has been identified in sporadic and familial ALS, indicating the existence of a common pathogenic pathway. These pathophysiological insights have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.