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. Author manuscript; available in PMC: 2020 Aug 1.
Published in final edited form as: Curr Opin Neurobiol. 2019 May 6;57:171–178. doi: 10.1016/j.conb.2019.03.006

Figure 3. An integrated model of axon degeneration pathways.

Figure 3

Axon injury triggers NMNAT2 loss, SARM1 activation and MAPK activation in the axon. PHR1 and Skp1a also speed NMNAT2 turnover. Depletion of NMNAT2 may lead to SARM1 activation. The position of MAPK pathway in relation to SARM1 and NMNAT2 is still controversial. Nevertheless, MAPK activation results in SCG10 loss. SARM1 activation and NMNAT2 loss together lead to NAD+ depletion and NMN accumulation in the axon, which then causes ATP depletion and energy deficit. Axed is a convergence point downstream of SARM1 and NMNAT2 in flies, but its exact function is still unclear. Energetic failure leads to calpain activation. These pathways then culminate in cytoskeleton degradation and eventually lead to irreversible fragmentation of the injured axon.