Therapeutic strategies for neurological disorders are now spreading in many directions. Previously, the removal of regeneration-inhibitory environments in the brain, together with the introduction of regeneration-promotive characteristics of the peripheral nerves has been explored. More recently, the effect of transplantation of stem cell-derived cells on traumatic injury and neurodegenerative disorders has been examined. Among various approaches aimed at a recovery from neurodegeneration, neuronal protection based on the understanding of degeneration mechanisms is an attractive alternative, especially for neurodegenerative disorders. Axon degeneration is a hallmark of many neurological disorders, including neuropathies and neurodegenerative diseases. Previous studies have shown that subcellular signaling which promotes axonal degeneration is independent from the typical cell death signal. Whereas, axonal protection mechanism, as shown in a naturally occurring mutant strain wallerian degeneration slow (wlds) mice, can save both axons and cell bodies from some types of insults, but the existence of common regulatory mechanism(s) between Wallerian degeneration and neuronal apoptosis remains to be fully elucidated. In this chapter, we introduce a general overview of both well-established and newly discovered pathways that control the progression of Wallerian degeneration, and we also describe how E3 ubiquitin ligase zinc and ring finger 1 (ZNRF1) functions as a critical mediator for neurodegenerative pathways, Wallerian degeneration and neuronal apoptosis, by translating oxidative stress into subcellular signaling in neurons. Our results presented here, suggest that the pathophysiological significance of ZNRF1-mediated signaling in the regulation of both Wallerian degeneration and neuronal apoptosis is a potential therapeutic avenue against neurodegenerative disorders.