FIGURE 3.

Calcium dysregulation, ER stress and mitochondrial impairment are major components of excitotoxicity in motor neurons. Mitochondrial dysfunction causes activation of proteolytic and ROS generating-generating enzyme systems. Mutant SOD1 forms insoluble aggregates in mitochondria at the surface of the outer membrane. Motor neuron might also undergo transcriptional dysregulation and abnormal RNA processing which together with depleted ER Ca²⁺ levels and overproduction of ROS contribute to aberrant protein folding. Aberrant proteins form aggregates leading to ER stress and ultimately activating apoptotic pathways, especially when the unfolded protein response is exhausted. Impaired axonal transport may also contribute to an energy deficit in the distal axon and the dying back axonopathy that is observed in ALS.