Acquired axonal degeneration and regeneration

Axonal degeneration is a common feature of traumatic, ischemic, inflammatory, toxic, metabolic, genetic, and neurodegenerative disorders affecting the CNS and the peripheral nervous system (PNS). The typical example is Wallerian degeneration (WD), which results from traumatic or ischemic injuries that disconnect the neuronal cell body from the distal segment of the axon. A WD-like degeneration occurs in inflammatory-demyelinating and neurodegenerative diseases associated with interruption of axonal transport and formation of large axonal swelling or spheroids. Dying-back refers to the progressive distal to proximal axonal degeneration that results from metabolic, toxic, or degenerative disorders. Axonal degeneration proceeds via a regulated axonal death program that is independent of the molecular events that control apoptosis or autophagy in the cell body and reflects the convergence of 3 mechanisms: impaired axonal transport, mitochondrial dysfunction, and increase in intra-axoplasmic calcium (Ca2+). WD is no longer considered the consequence of failure to deliver structural components but rather of inability to deliver a putative natural inhibitor of the death program in the axon. The discovery of the mouse WlD s mutant, which has prolonged axonal survival following nerve transection, indicates that axons contain an intrinsic protective mechanism. Retrograde signaling following injury triggers profound changes in transcription and translation in the neuronal cell body, which may drive compensatory axon growth leading to sprouting or, less commonly, axonal regeneration. Axonal regeneration may occur in the PNS but is often incomplete; regeneration is much less likely to occur in the CNS, in part due to the presence of inhibitory molecules from oligodendrocytes and reactive astrocytes. The importance of axonal degeneration as a fundamental mechanism of neurologic disease and therapeutic target for neuroprotection is the focus of many comprehensive reviews.1–16