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

Di Stefano, M., Loreto, A., Orsomando, G., Mori, V., Zamporlini, F., Hulse, R.P. ORCID: 0000-0002-5193-9822, Webster, J., Donaldson, L.F., Gering, M., Raffaelli, N., Coleman, M.P., Gilley, J. and Conforti, L., 2017. NMN deamidase delays Wallerian degeneration and rescues axonal defects caused by NMNAT2 deficiency in vivo. Current Biology, 27 (6), pp. 784-794. ISSN 0960-9822

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Abstract

Highlights:
• NMN deamidase delays Wallerian degeneration in vivo in mice and zebrafish
• NMN deamidase reduces NMN accumulation in transected nerves
• NMN deamidase protects axons against non-injury insults
• NMN deamidase rescues axonal defects and lethality in NMNAT2-deficient mice.
Summary:
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 it 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 three weeks, even when expressed at a low level. Remarkably, NMN deamidase also rescues axonal outgrowth and perinatal lethality in a dose-dependent manner in mice lacking NMNAT2. 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.

Item Type: Journal article
Publication Title: Current Biology
Creators: Di Stefano, M., Loreto, A., Orsomando, G., Mori, V., Zamporlini, F., Hulse, R.P., Webster, J., Donaldson, L.F., Gering, M., Raffaelli, N., Coleman, M.P., Gilley, J. and Conforti, L.
Publisher: Elsevier
Date: 20 March 2017
Volume: 27
Number: 6
ISSN: 0960-9822
Identifiers:
NumberType
10.1016/j.cub.2017.01.070DOI
S0960982217301355Publisher Item Identifier
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 04 Jan 2018 10:05
Last Modified: 04 Jan 2018 10:07
URI: http://irep.ntu.ac.uk/id/eprint/32276

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