Therapeutic opportunities and pitfalls in the treatment of axon degeneration

Purpose of review The current review analyzes recent findings that suggest that axon degeneration is a druggable process in the treatment of neurodegenerative disorders and a subset of traumas. Recent findings Emerging evidence reveals that axon degeneration is an active and regulated process in the early progression of some neurodegenerative diseases and acute traumas, which is orchestrated through a combination of axon-intrinsic and somatically derived signaling events. The identification of these pathways has presented appealing drug targets whose specificity for the nervous system and phenotypes in mouse models offers significant clinical opportunity. As the biology of axon degeneration becomes clear, so too has the realization that the pathways driving axon degeneration overlap in part with those that drive neuronal apoptosis and, importantly, axon regeneration. Axon-specific disorders like those seen in CIPN, where injury signaling to the nucleus is not a prominent feature, have been shown to benefit from disruption of Sarm1. In injury and disease contexts, where involvement of somatic events is prominent, inhibition of the MAP Kinase DLK exhibits promise for neuroprotection. Here, however, interfering with somatic signaling may preclude the ability of an axon or a circuit to regenerate or functionally adapt following acute injuries.