Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca2+ Influx but Only Modestly Influenced by Mitochondria

Axon injury leads to rapid depletion of NAD-biosynthetic enzyme NMNAT2 and high levels of its substrate, NMN. We proposed a key role for NMN in Wallerian degeneration but downstream events and their relationship to other mediators remain unclear. Here, we show, in vitro and in vivo, that axotomy leads to a late increase in intra-axonal Ca2+, abolished by pharmacological or genetic reduction of NMN levels. NMN requires the pro-degenerative protein SARM1 to stimulate Ca2+ influx and axon degeneration. While inhibition of NMN synthesis and SARM1 deletion block Ca2+ rise and preserve axonal integrity, they fail to prevent early mitochondrial dynamic changes. Furthermore, depolarizing mitochondria does not alter the rate of Wallerian degeneration. These data reveal that NMN and SARM1 act in a common pathway culminating in intra-axonal Ca2+ increase and fragmentation and dissociate mitochondrial dysfunctions from this pathway, elucidating which steps may be most effective as targets for therapy. [Display omitted] •NMN stimulates an intra-axonal Ca2+ rise shortly preceding axonal fragmentation•NMN requires SARM1 to induce Ca2+ rise and axon degeneration•The extracellular environment is the main source of NMN-induced axonal Ca2+ rise•Mitochondrial dynamic changes are not causative in NMN-induced degeneration Loreto et al. show that NAD-precursor NMN, previously reported to induce Wallerian degeneration, stimulates a Ca2+ rise in injured axons, which requires the protein SARM1 and shortly precedes fragmentation. Changes in mitochondrial dynamics are not associated with degeneration. These results advance our understanding of axon degeneration mechanisms relevant to neurodegeneration.