Fig. 3 |. A working model of the Wallerian degeneration pathway.

The figure shows current knowledge of the factors that determine nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) activity in axons, how NMNAT2 loss activates sterile-α and Toll/interleukin 1 receptor (TIR) motif containing protein 1 (SARM1) and events downstream of SARM1 leading to axon degeneration. Various factors disrupt the delivery of functional NMNAT2 to axons. NMNAT2 turnover is mediated by the mitogen-activated protein kinases (MAPK) dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK), as well as a ubiquitin ligase complex consisting of MYC-binding protein 2 (MYCBP2), s-phase kinase-associated protein 1A (SKP1A) and F-box protein 45 (FBXO45)³⁸. In combination, this reduces NMNAT2 levels and causes downstream activation of SARM1, probably as a result of increased levels of nicotinamide mononucleotide (NMN) but potentially also in other ways³⁵. The combined effect of decreased NMNAT2 and increased activation of SARM1 leads to a great decrease in axonal nicotinamide adenine dinucleotide (NAD), which may itself cause axon degeneration through ATP synthesis failure²⁵. Alternatively, other SARM1 substrates or its calcium mobilizing products could be important for the later stages of Wallerian degeneration. In Drosophila melanogaster, there is also an as-yet undefined role for Axundead (Axed) in Wallerian axon degeneration¹⁹. ADPR, ADP-ribose; cADPR, cyclic ADP-ribose.