NAD⁺, Axonal Maintenance, and Neurological Disease

The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD⁺) metabolism for axonal self-destruction, the complex roles of NAD⁺ in axonal viability and disease have become research priority. The discoveries of the protective Wallerian degeneration slow (Wld^S) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD⁺ in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD⁺ hydrolase and sensor of NAD⁺ metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD⁺ and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD⁺ metabolism. Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD⁺ metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. There is a need for clarification of the distinct roles of NAD⁺ metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD⁺ metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. Antioxid. Redox Signal. 39, 1167-1184.