Figure 2.

A scheme of the SOD1-dependent molecular mechanisms involved in motoneuron death in ALS. SOD1-dependent pathways may damage motoneurons increasing ROS production through RAC activation, that impairs protein export, by protein aggregation in the ER–Golgi apparatus and by inducing deranged mitochondrial activity generating further ROS production Excitotoxicity induced by glutamatergic synapses hyper-stimulation or by impaired glutamate transporter into glial cells and presynaptic membrane, also contributes to motoneuron death. Similar effects could be due to SOD1 and even more due to SOD1^G93A interaction with metabotropic muscarinic M1 receptor. Both mechanisms generate excitotoxicity by increasing intracellular Ca²⁺ concentration that alters multiple Ca²⁺-dependent signaling pathways. Activation of glial cells, generating pro-inflammatory cytokines and toxic factors, also contributes to the progression of ALS. Others factors involved in the pathogenesis of ALS progression are not represented. The red arrows indicate signal propagation inside axon; the increasing black indicate higher concentration. Image has been partially created by using BioRender.com.