NAD⁺-dependent mechanism of pathological axon degeneration

Pathological axon degeneration is broadly observed in neurodegenerative diseases. This unique process of axonal pathology could directly interfere with the normal functions of neurocircuitries and contribute to the onset of clinical symptoms in patients. It has been increasingly recognized that functional preservation of axonal structures is an indispensable part of therapeutic strategies for treating neurological disorders. In the past decades, the research field has witnessed significant breakthroughs in understanding the stereotyped self-destruction of axons upon neurodegenerative insults, which is distinct from all the known types of programmed cell death. In particular, the novel NAD⁺-dependent mechanism involving the WLD^s, NMNAT2, and SARM1 proteins has emerged. This review summarizes the landmark discoveries elucidating the molecular pathway of pathological axon degeneration and highlights the evolving concept that neurodegeneration would be intrinsically linked to NAD⁺ and energy metabolism.