Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration

Axon degeneration is caused by multiple chemotherapeutic agents and is a hallmark of chemotherapy-induced peripheral neuropathy (CIPN). CIPN is associated with the loss of the essential metabolite nicotinamide adenine dinucleotide (NAD⁺), a vital metabolite involved in energy homeostasis, but whether NAD⁺ loss or the accumulation of an NAD⁺ precursor, nicotinamide mononucleotide (NMN), is responsible for axon degeneration is controversial. We found that axon degeneration caused by vincristine, a widely used chemotherapeutic agent, could be ameliorated by forcing peripheral neurons to use an NAD⁺ biosynthetic pathway that bypasses NMN formation. This strategy provides an approach for preventing CIPN.