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NMN deamidase delays Wallerian degeneration and rescues axonal defects caused by NMNAT2 deficiency in vivo

Di Stefano, Michele; Loreto, Andrea; Orsomando, Giuseppe; Mori, Valerio; Zamporlini, Federica; Hulse, Richard P.; Webster, Jamie; Donaldson, Lucy F.; Gering, Martin; Raffaelli, Nadia; Coleman, Michael P.; Gilley, Jonathan; Conforti, Laura


Michele Di Stefano

Andrea Loreto

Giuseppe Orsomando

Valerio Mori

Federica Zamporlini

Richard P. Hulse

Jamie Webster

Professor of Sensory Physiology

Nadia Raffaelli

Michael P. Coleman

Jonathan Gilley

Laura Conforti


Axons require the axonal NAD-synthesizing enzyme NMNAT2 to survive. Injury or genetically-induced depletion of NMNAT2 triggers axonal degeneration or defective axon growth. We have previously proposed that axonal NMNAT2 primarily promotes axon survival by maintaining low levels of its substrate NMN, rather than generating NAD; however, this is still debated. NMN deamidase, a bacterial enzyme, shares NMN-consuming activity with NMNAT2, but not NAD-synthesizing activity, and delays axon degeneration in primary neuronal cultures. Here, we show that NMN deamidase can also delay axon degeneration in zebrafish larvae and in transgenic mice. Like overexpressed NMNATs, NMN deamidase reduces NMN accumulation in injured mouse sciatic nerves and preserves some axons for up to 3 weeks, even when expressed at a low level. Remarkably, NMN deamidase also rescues axonal outgrowth and perinatal lethality in mice lacking NMNAT2 in a dose-dependent manner. These data further support a pro-degenerative effect of accumulating NMN in axons in vivo. The NMN deamidase mouse will be an important tool to further probe the mechanisms underlying Wallerian degeneration and its prevention.


Di Stefano, M., Loreto, A., Orsomando, G., Mori, V., Zamporlini, F., Hulse, R. P., …Conforti, L. (2017). NMN deamidase delays Wallerian degeneration and rescues axonal defects caused by NMNAT2 deficiency in vivo. Current Biology, 27(6), 784-794.

Journal Article Type Article
Acceptance Date Feb 1, 2017
Online Publication Date Mar 2, 2017
Publication Date Mar 20, 2017
Deposit Date Feb 27, 2017
Publicly Available Date Mar 2, 2017
Journal Current Biology
Print ISSN 0960-9822
Electronic ISSN 1879-0445
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 27
Issue 6
Pages 784-794
Keywords axon degeneration; Wallerian degeneration; NMNAT2; NMNAT; NMN; NAD; NMN deamidase; WLDs; SARM1; neurodegeneration
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Additional Information This article is maintained by: Elsevier; Article Title: NMN Deamidase Delays Wallerian Degeneration and Rescues Axonal Defects Caused by NMNAT2 Deficiency InVivo; Journal Title: Current Biology; CrossRef DOI link to publisher maintained version:; Content Type: article; Copyright: © 2017 The Authors. Published by Elsevier Ltd.


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