Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons (MN). The disease is characterized by moderate and progressive dysfunction and loss of motor neurons. In the most advanced stages, patients develop symptoms of dyspnea and dysphagia. Most patients die of respiratory failure .

Key figures about Amyotrophic Lateral Sclerosis

ALS is considered a rare disease because of its extremely low prevalence, with 2 to 3 cases per 100,000 people. The cause is unknown in 90-95% of cases (sporadic ALS), and only 5-10% of cases are associated with known genetic mutations (familial ALS). Data from clinical studies show that ALS is linked to multiple mutations, the most common of which are C9orf72, SOD1 (superoxide dismutase 1), FUS (Fused in Sarcoma), and TDP-43 (TAR DNA Binding Protein 43), as well as enhanced neuroinflammation. Even in the absence of known genetic alterations, there is immune dysregulation .

Immune dysregulation – results in increased central and peripheral inflammation

Although immune alterations do not trigger ALS, numerous studies indicate that activation of microglia in the central nervous system (CNS) occurs before or at the same time as the onset of clinical symptoms and increases throughout the disease. The in vivo activation state of cells involved in ALS is characterized by a continuum between the neuroprotective and neurotoxic states. As the disease progresses, astrocytes are activated, either through activated microglia or independently through the release of compounds from motor neurons. Thus, these glial cells express proinflammatory cytokines (TNF-α, IL-1β, IL-12, IFN-γ, IL-6), mitogenic factors (MCP-1, M-CSF), and neurotrophic factors (IGF-1), including molecules involved in oxidative stress (cyclo-oxygenase-2, ROS, NOS) that can promote a neurotoxic environment. When the critical threshold is reached, the pathological process becomes irreversible and leads to the death of non-autonomous motor neurons in ALS patients.

Neuroinflammation is not limited to the CNS, it needs a systemic inflammatory response to enable the local inflammation to take place. One study has shown elevated levels of TNF-α, IL-17, IFN-γ factors, and peripheral immune cells, T cells, in the blood and CSF of patients. Neuroinflammation of the CNS therefore causes an increase in proinflammatory T-cell infiltration as the disease progresses. The hypothesis put forward is that due to motor nerve damage resulting from misfolded SOD1 and FUS, and TDP-43 aggregation, specific antigens are released and processed by antigen-presenting cells (APCs). APCs are believed to induce the priming of specific T cells and their recruitment into the CNS, which promotes inflammation of the MNs, leading to their death .