Proposed mechanisms of toxicity in SOD1-mediated ALS. (A) Excitotoxicity is the hyperactivation of motor neurons resulting from failure to rapidly remove neurotransmitter glutamate from synapses due to deficiency in the glutamate transporter EAAT2 in the neighboring astrocytes. (B) ER stress is induced by abnormal interactions of mutant SOD1 with ER proteins (see text for details). (C) Proteasome inhibition due to “overload” of the proteasome degradation pathway with ubiquitinated misfolded protein aggregates may damage astrocytes and motor neurons. (D) Mitochondrial dysfunction mediated by mutant SOD1 deposition on the mitochondrial membrane provokes release of cytochrome c in motor neurons, whereas in astrocytes it leads to nitroxidative stress. (E) Toxic extracellular mutant SOD1 is secreted from motor neurons and astrocytes (not depicted) after interaction with components of neurosecretory vesicles. (F) Superoxide production from microglia or astrocytes can damage neighboring motor neurons. (G) Altered axonal transport including an increase in retrogradely transported stress-related proteins was reported in mutant SOD1-expressing motor neurons. (H) Synaptic vesicle defects such as stalling and loss from distal synapse in vulnerable motor neurons is an early event in ALS. (I) Loss of tight junction proteins within capillary endothelial cells results in the disruption of the blood–spinal cord barrier and the occurrence of microhemorrhages within the spinal cord well before disease onset.