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Review
. 2019 Aug:57:171-178.
doi: 10.1016/j.conb.2019.03.006. Epub 2019 May 6.

Mechanisms of injury-induced axon degeneration

Chen Ding  1 , Marc Hammarlund  2
Affiliations
Review

Mechanisms of injury-induced axon degeneration

Chen Ding et al. Curr Opin Neurobiol. 2019 Aug.

Abstract

Injury-induced axon degeneration in model organisms and cell culture has emerged as an area of growing interest due to its experimental tractability and to the promise of identifying conserved mechanisms that mediate axon loss in human disease. Injury-induced axon degeneration is also observed within the well-studied process of Wallerian degeneration, a complex phenomenon triggered by axon injury to peripheral nerves in mammals. Recent studies have led to the identification of key molecular components of injury-induced axon degeneration. Axon survival factors, such as NMNAT2, act to protect injured axons from degeneration. By contrast, factors such as SARM1, MAPK, and PHR1 act to promote degeneration. The coordinated activity of these factors determines axon fate after injury. Since axon loss is an early feature of neurodegenerative diseases, it is possible that understanding the molecular mechanism of injury-induced degeneration will lead to new treatments for axon loss in neurodegenerative disease. Here, we discuss the critical pathways for injury-induced axon degeneration across species with an emphasis on their interactions in an integrated signaling network.

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Conflict of interest statement

Declarations of interest

None

Figures

Figure 1
Figure 1. The NAD+ synthesis and breakdown pathways
NAD+ can be synthesized from NMN by NMNAT and WLDS, or from NaAD by NAD synthetase. NRK converts NR to NMN and NAR to NaMN. NMN deamidase (NMN DD) is a bacterial enzyme that converts NMN to NaMN. NaMN can further be converted to NaAD by NMNAT. Axon injury activates SARM1, which then cleaves NAD+ into Nam, ADPR and cADPR. Nam is converted to the NAD+ precursor NMN by NAMPT, which can be inhibited by FK866.
Figure 2
Figure 2. SARM1 structure and function
A. The autoinhibitory SARM1 N terminus contains a mitochondria localization signal and ARM domains. The two SAM domains mediate multimerization. The C terminal TIR domain possesses intrinsic NAD+ cleavage activity. B. SARM1 forms multimers. The TIR domains are inhibited in normal conditions, possibly through direct interactions with the N terminus. Axon injury activates SARM1 by releasing the auto-inhibition on the TIR domains. Activated TIRs then cleave NAD+ into Nam, ADPR and cADPR and trigger axon degeneration.
Figure 3
Figure 3. An integrated model of axon degeneration pathways
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.
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