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

Loreto, Andrea; Di Stefano, Michele; Gering, Martin; Conforti, Laura

Abstract

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.

Citation

Loreto, A., Di Stefano, M., Gering, M., & Conforti, L. (2015). Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca²⁺ Influx but Only Modestly Influenced by Mitochondria. Cell Reports, 13(11), 2539-2552. https://doi.org/10.1016/j.celrep.2015.11.032

• Journal Article Type: Article
• Acceptance Date: Nov 6, 2015
• Online Publication Date: Dec 10, 2015
• Publication Date: Dec 22, 2015
• Deposit Date: Mar 26, 2018
• Publicly Available Date: Oct 15, 2018
• Journal: Cell Reports
• Print ISSN: 2211-1247
• Electronic ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 11
• Pages: 2539-2552
• DOI: https://doi.org/10.1016/j.celrep.2015.11.032
• Public URL: https://nottingham-repository.worktribe.com/output/1115085
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2211124715013479
• PMID: 26686637
• Contract Date: Oct 15, 2018