Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, causing progressive muscle atrophy and weakness, fatigue, and problems with swallowing and respiration. ALS is a devastating condition. Over 60% of patients die within 3 years of presentation of the first symptoms, typically as the result of respiratory failure. Only 5 to 10% of patients survive beyond 10 years. In contrast to other neurodegenerative diseases, the risk of developing ALS peaks between the ages of 50 years and 75 years, and declines thereafter. The prevalence of ALS, an orphan disease, is relatively low at about 5-6 per 100,000 people. Yet, an estimated 15,000 people in Europe are still being diagnosed with ALS every year. There is no adequate treatment of ALS. The only registered drug extends life by a mere 2 to 3 months, and care for people with ALS largely relies on palliative treatments.

The cause of ALS is unknown, but it is generally believed that abnormal accumulation of glutamate in the CNS plays a major role in causing motor neurons to die. Glutamate is an important signaling substance in the CNS, which controls a large variety of neuronal functions. In a healthy CNS, levels of glutamate are carefully controlled by transporter proteins on astrocytes that remove excess glutamate from the extracellular space and metabolize it. In people with ALS, astrocytes carry much less of the glutamate transporters on their surface, which leads to glutamate accumulating to lethal levels for motor neurons.

Another factor in ALS is the occurrence of mutations in the gene encoding for the copper/zinc superoxide dismutase 1 (SOD1). SOD1 is a cytoplasmic protein that controls the potentially dangerous effects of reactive oxygen species that, like glutamate, are widely used as signaling molecules in the CNS. In many cases of ALS, something is wrong with SOD1 as the result of mutations or chemical changes to the protein. In different ways, the faulty protein can trigger inflammatory reactions, for example by forming aggregates that provoke a pro-inflammatory response by surrounding microglia, the macrophages of the CNS. The disease process of ALS can be at least in part mimicked in mice by introducing genes that encode for mutant SOD1 proteins. This model offers a way to examine factors leading to ALS, and ways to counteract the disease process. Finally, also the peripheral immune system is likely involved in ALS. Over the past decade, it has become clear that a healthy CNS heavily relies on a healthy immune system, and especially on adequate functioning of regulatory T cells. In animal models for ALS, regulatory T cells reduce progression and improve survival.