Dysregulation of NAD⁺ Metabolism Induces a Schwann Cell Dedifferentiation Program

The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD⁺) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD⁺ metabolism in SC functions <i>in vivo</i> by mutating NAMPT, the rate-limiting enzyme of NAD⁺ biosynthesis, specifically in SCs. NAMPT SC knock-out male and female mice (NAMPT SCKO mice) had delayed SC maturation in development and developed hypomyelinating peripheral neuropathy without axon degeneration or decreased SC survival. JUN, a master regulator of SC dedifferentiation, is elevated in NAMPT SCKO SCs, suggesting that decreased NAD⁺ levels cause them to arrest at an immature stage. Nicotinic acid administration rescues the NAD⁺ decline and reverses the SC maturation defect and the development of peripheral neuropathy, indicating the central role of NAD⁺ in PNS development. Upon nicotinic acid withdrawal in adulthood, NAMPT SCKO mice showed rapid and severe peripheral neuropathy and activation of ERK/MEK/JUN signaling, which in turn promotes SC dedifferentiation. These data demonstrate the importance of NAD⁺ metabolism in SC maturation and nerve development and maintenance and suggest that altered SC NAD⁺ metabolism could underlie neuropathies associated with diabetes and aging. <b>SIGNIFICANCE STATEMENT</b> In this study, we showed that Schwann cell differentiation status is critically dependent on NAD⁺ homeostasis. Aberrant regulation of NAD⁺ biosynthesis via NAMPT deletion results in a blockade of Schwann cell maturation during development and severe peripheral neuropathy without significant axon loss. The phenotype can be rescued by supplementation with nicotinic acid; however, withdrawal of nicotinic acid leads to Schwann cell dedifferentiation, myelination defects, and death. These results provide new therapeutic possibilities for peripheral neuropathies associated with NAD⁺ decline during aging or diabetes.