Distal axons of severed neurons undergo a stereotypic degeneration process consisting of thinning, beading, and fragmentation, which is commonly referred to as Wallerian Degeneration (WD). In mice, a dominant mutation causing the chimeric protein WLDS (Slow Wallerian Degeneration), that includes part of the ubiquitin fusion degradation protein 2a and the complete sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), confers a strong delay of axonal degeneration. Through the identification and molecular cloning of WldS, axonal degeneration has been shown to be an active process that is controlled by a genetic pathway. Furthermore, studies on axonal degeneration in mice, rats, fruit flies, and zebrafish have shown that this process is highly conserved, and have identified several of the genes involved, including Nmnat2/nmat-2, Sarm1/tir-1 and Wallenda/dlk-1. However, although severed C. elegans axons present a morphologically similar degeneration pattern to other organisms, the existence of a similar active axonal degeneration pathway in this tractable model have yet to be investigated. To address this gap, we have characterized axonal degeneration in the PLM mechanosensory neurons and developed strains overexpressing WLDS as well as the endogenous C. elegans Nmnat homologs (NMAT-1 and NMAT-2) in these cells. We have investigated the effects of these molecules, as well as of TIR-1 and DLK-1, on axonal degeneration following laser-induced injury. Across a wide range of experimental paradigms, including differing expression levels, larval stages, and neuronal classes, we do not find a delay in axonal degeneration. However, we find that WldS overexpression can protect the neuron against necrosis induced by the dominant
mec-4d mutation (which causes the MEC-4 calcium channel to be constitutively open), similarly to previous work with NMAT-2 (Calixto et al., 2012). Therefore we propose that axonal degeneration in C. elegans, does not proceed through the active molecular mechanisms of the WD pathway as seen in mammals, zebrafish and fruit flies, suggesting that in C. elegans either this is a passive process or that there is another axon destruction program yet to be determined.