The Role of NMNAT2/SARM1 in Neuropathy Development

Simple Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of various cancer chemotherapy treatments, often leading to dose reduction or treatment discontinuation. The lack of a comprehensive understanding of its underlying mechanisms has hindered the development of effective CIPN treatments. Recent investigations focusing on axon degeneration mechanisms have identified NMNAT2 and SARM1 as key mediators of injury-induced axonal degeneration. In this review, our objective is to examine various studies shedding light on the interplay between NMNAT2 and SARM1 proteins and their roles in the progression of CIPN. We discuss three main aspects of the NMNAT2/SARM1 interplay: (1) the balance between NMNAT2 and SARM1 and their direct impact on NAD+ synthesis at the cellular level and axonal translocation; (2) the regulation by NMNAT2 and SARM1 of crucial downstream players implicated in neuronal cell death; (3) the role of SARM1 in activating immune cells, potentially contributing to the development of neuroinflammation. Additionally, we review the existing literature that explores the involvement of NMNAT2 and SARM1 in CIPN development and provide a summary of information on available inhibitors as potential therapeutic options.Abstract Chemotherapy-induced peripheral neuropathy (CIPN) commonly arises as a side effect of diverse cancer chemotherapy treatments. This condition presents symptoms such as numbness, tingling, and altered sensation in patients, often accompanied by neuropathic pain. Pathologically, CIPN is characterized by an intensive "dying-back" axonopathy, starting at the intra-epidermal sensory innervations and advancing retrogradely. The lack of comprehensive understanding regarding its underlying mechanisms explains the absence of effective treatments for CIPN. Recent investigations into axon degeneration mechanisms have pinpointed nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha and TIR motif-containing 1 protein (SARM1) as pivotal mediators of injury-induced axonal degeneration. In this review, we aim to explore various studies shedding light on the interplay between NMNAT2 and SARM1 proteins and their roles in the progression of CIPN.