FIGURE 3.

Potential mechanisms by which chronically demyelinated axons degenerate. Schematic of a chronically demyelinated intact axon and an additional demyelinated axon undergoing degeneration. Demyelinated axons are exposed to inflammatory mediators including ROS/RNS in MS, have reduced axonal transport, and may have synapse dysfunction/loss. The chronically demyelinated axon is likely to be in an energy crisis in which the lack of oligodendrocyte support coupled with mitochondrial damage and increased energetic demands to sustain AP propagation means there is a shortfall of ATP necessary to drive the Na⁺K⁺ATPase. This causes a reversal of the NCX to remove Na⁺ from the axon, but at the cost of calcium entry. Disruption of the plasma membrane, and calcium entry through calcium-permeable channels including glutamate receptors, ASICs, VGCC and mitochondrial release cause calcium to accumulate in the axon. Intra-axonal calpains are activated when calcium accumulates to high levels and begin the process of degeneration and breakdown critical cytoskeletal structures including microtubules. Activation of cell-stress pathways and the unfolded protein response also are present in many demyelinated neurons that are susceptible to degeneration. Faded text and indicates low activity or levels, bolded text or thick arrows indicates increased activated.