[2] Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event.

It occurs in the section of the axon distal to the site of injury and usually begins within 24–36 hours of a lesion.

They finally align in tubes (Büngner bands) and express surface molecules that guide regenerating fibers.

Regeneration is efficient in the PNS, with near complete recovery in case of lesions that occur close to the distal nerve terminal.

One crucial difference is that in the CNS, including the spinal cord, myelin sheaths are produced by oligodendrocytes and not by Schwann cells.

He then observed the distal nerves from the site of injury, which were separated from their cell bodies in the brain stem.

The degenerating axons formed droplets that could be stained, thus allowing for studies of the course of individual nerve fibres.

[9] A brief latency phase occurs in the distal segment during which it remains electrically excitable and structurally intact.

The disintegration is dependent on ubiquitin and calpain proteases (caused by influx of calcium ion), suggesting that axonal degeneration is an active process and not a passive one as previously misunderstood.

PNS is much faster and efficient at clearing myelin debris in comparison to CNS, and Schwann cells are the primary cause of this difference.

In PNS, the permeability increases throughout the distal stump, but the barrier disruption in CNS is limited to just the site of injury.

[13] Although MAPK activity is observed, the injury sensing mechanism of Schwann cells is yet to be fully understood.

The myelin sheaths separate from the axons at the Schmidt-Lanterman incisures first and then rapidly deteriorate and shorten to form bead-like structures.

[11] However, the macrophages are not attracted to the region for the first few days; hence the Schwann cells take the major role in myelin cleaning until then.

Schwann cells have been observed to recruit macrophages by release of cytokines and chemokines after sensing of axonal injury.

Delayed macrophage recruitment was observed in B-cell deficient mice lacking serum antibodies.

While Schwann cells mediate the initial stage of myelin debris clean up, macrophages come in to finish the job.

This proliferation could further enhance the myelin cleaning rates and plays an essential role in regeneration of axons observed in PNS.

[17] Experiments in Wallerian degeneration have shown that upon injury oligodendrocytes either undergo programmed cell death or enter a state of rest.

In contrast to PNS, microglia play a vital role in CNS Wallerian degeneration.

Differentiating phagocytic microglia can be accomplished by testing for expression of major histocompatibility complex (MHC) class I and II during Wallerian degeneration.

Nerve fibroblasts and Schwann cells play an important role in increased expression of NGF mRNA.

Mice belonging to the strain C57BL/Wlds have delayed Wallerian degeneration,[28] and, thus, allow for the study of the roles of various cell types and the underlying cellular and molecular processes.

[6] The protective effect of the WldS protein has been shown to be due to the NMNAT1 region's NAD+ synthesizing active site.

However, later studies showed that NMNAT1 is protective when combined with an axonal targeting peptide, suggesting that the key to the protection provided by WldS was the combination of NMNAT1's activity and the axonal localization provided by the N-terminal domain of the chimeric protein.

The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of WldS.

[43] SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration.

[44] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity.

[44] The activity of SARM1 helps to explain the protective nature of the survival factor NMNAT2, as NMNAT enzymes have been shown to prevent SARM1-mediated depletion of NAD+.

[46] This relationship is further supported by the fact that mice lacking NMNAT2, which are normally not viable, are completely rescued by SARM1 deletion, placing NMNAT2 activity upstream of SARM1.