Wallerian Degeneration and Nerve Regeneration—A Review of Cellular and Molecular Events

Wallerian degeneration (WD), which occurs distal to peripheral nerve injury, is a tightly regulated process. Axonal degeneration during the onset of WD represents a self-destructive process that begins with an early phase and progresses to an execution phase characterized by fragmentation of axons and myelin sheaths. Efficient clearance of axonal and myelin debris, together with the reprogramming of Schwann cells and macrophages into a repair phenotype, constitutes a critical extrinsic prerequisite for successful axonal regeneration. In parallel, signaling molecules produced during WD trigger intrinsic responses in injured neurons that are essential for neuronal survival and the initiation of the regenerative program. This review provides an overview of the key events involved in WD, which are often studied separately, with the aim of elucidating their interrelationships and their impact on nerve regeneration. Such an integrated overview may aid in identifying molecular targets for the development of novel therapeutic strategies to enhance axonal regeneration.