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Figure 1. Systemic inflammation is initiated in motor axon terminals of the peripheral compartment In ALS patients. On the lower panel L- and R-sides we present ultrastructural illustrations of terminals from two different ALS patients^[5]. Calcium precipitates are present in intraluminal membrane bound organelles and mitochondria. The dysfunctional mitochondria induce reactive oxygen species (ROS) and lipid peroxides, and promote ferroptosis, which activates macrophages and T lymphocytes. In turn, the activation by oxidized lipids induces macrophage production and secretion of IL-6, IL-1β, and TNF-α, followed by synthesis and release of acute phase proteins by the liver. The gut microbiome directly interacts with the immune system at this early stage. In the upper panel neuroinflammation in the CNS compartment is the consequence of “dying back” from the axon terminal as well as the spread of pro-inflammatory immune cells from the periphery to the CNS. The spread of pro-inflammatory immune cells from the CNS back to the periphery then promotes a self-propagating cytotoxic cascade. The result is activation of programmed cell death pathways involving apoptosis, necroptosis, as well as ferroptosis (Modified from Figure 1, Ref. 3^[3]). ALS: Amyotrophic lateral sclerosis; CNS: central nervous system.