The specificity of the toxic effect of SOD1 mutations on motor neurons arises from the convergence of several risk factors
a) Initially, a lower motor neuron receives signals to fire by the release of glutamate (Glu) from an upstream neuron, either an upper motor neuron or an interneuron. This signal is converted within the motor neuron into action potentials that stimulate the release of acetylcholine (orange) at its axon terminus, triggering muscle contraction.
b) In neurons and astrocytes, superoxide dismutase 1 (SOD1) accumulates during aging, forming mutant SOD1 aggregates, either by an inherently unstable conformation or by self-induced oxidative damage. This triggers a loss of overall protein-folding chaperone activity and inhibits the removal of other damaged proteins by choking the 20S proteasome. Neurofilaments, especially in axons, become disorganized, inhibiting transport of components along the axon. Caspase 1 is chronically activated.
c) Inhibition of chaperone and proteasome activity, loss of axonal transport capacity and an accelerated SOD1-mutant burden force chronic deficits in motor neurons. Similar damage in astrocytes suppresses the accumulation and activity of glutamate transporters (EAAT2) that are necessary for recovering synaptic glutamate and for preventing repetitive motor neuron firing. Such disproportionate firing produces excessive calcium entry through calcium-permeable glutamate receptors, activating caspase 3, which serves as the executioner for motor neuron death through the degradation of key cellular components.
