NAD+, Axonal Maintenance, and Neurological Disease

Athanasios S. Alexandris, Vassilis E. Koliatsos

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 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 WldS and of 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 NMNAT2 proteostasis in axons, the allosteric regulation of SARM1 by NAD+ andNMN, 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 need for clarification of the distinct roles of NAD+ metabolism in axonal maintenance as contrasted to WD. There is also need to better understand the role of NAD+ metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of CNS neurodegenerative diseases.