Figure 1: Working model of axon degeneration in CMT.

Axon degeneration in CMT occurs either as a primary axon-intrinsic process (CMT2) or secondary to defects extrinsic to axons (CMT1). Although it is unclear if these processes lead to activation of the molecular pathway that mediates Wallerian degeneration in CMT, there is ample evidence that NMNAT and SARM1 play a key role in acquired neuropathies where the primary process is slow distal axonal degeneration. An early event in this pathway is NMNAT2 depletion, which may be carried out by activation of MAPK signaling. Depletion of NMNAT2 leads to activation of SARM1, which may also occur independently of NMNAT2 depletion. SARM1 activation leads to a reduction in NAD⁺ levels due to the NADase activity of SARM1 and may also lead to additional MAPK signaling. Depletion of NAD⁺ leads to the loss of ATP, an energetic failure and Calpain activation. Calpain-mediated proteolysis then facilitates the structural breakdown of the axon. Activated MAPK signaling also depletes SCG10, a microtubule binding protein whose loss may contribute to axon degeneration. Intervention at several points along this pathway may offer potential therapeutic options (highlighted in red).