Figure 1.

Neuronal excitability and free radicals accelerate motor neuron degeneration in ALS. Excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors, mediated by glutamate, increase the influx of calcium ions (Ca²⁺). Ca²⁺ activates enzymes such as endonucleases, phospholipases and proteases, which may induce neuronal injury. Additionally, excessive activation of glutamate receptors generates free radicals and oxidative stress to thereby modulate DNA, RNA, lipids and proteins, increase glutamate concentration in the synaptic cleft and raise Ca²⁺ influx into the cells. These processes accumulate neurofilaments and increase proinflammatory cytokines, which might result in neurodegeneration. Moreover, accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of motor neurons potentially induces ER stress, and ER stress leads to the release of Ca²⁺ from the ER lumen.