Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis

The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics. This Review explores several key dysregulated pathways in ALS (RNA processing, proteostasis, metabolism and inflammation) as well as evolving efforts to develop effective therapeutics to restore cellular homeostasis. The authors also detail strategies that are likely to be required to improve clinical studies moving forwards.