Amyotrophic lateral sclerosis (ALS) is a relentless and progressive neurodegenerative disease that affects the motor neurons of the brain and spinal cord. Symptoms vary from person to person, some forms of ALS begin with limb weakness, while others start with bulbar symptoms. All forms ultimately lead to loss of independence and a markedly shortened lifespan. Median survival remains three to five years, and diagnosis is often delayed.

Despite this diversity, many patients share common downstream pathologies involving axonal injury, inflammation, and protein misfolding. SOD1 is a protective enzyme that helps cells manage oxidative stress. In ALS, structural changes can cause SOD1 to lose its proper function and misfold, taking on toxic conformations that disrupt cellular function. Such misfolded SOD1 can injure motor neurons, damage mitochondria and impair axonal transport. Pathology can spread by the seeding of SOD1 misfolding.

Misfolded SOD1 represents a powerful therapeutic opportunity. Across different presentations of ALS, misfolded SOD1 can amplify axonal injury and accelerate disease progression, making these toxic conformations an important target for intervention.