NMN Deamidase Delays Wallerian Degeneration and Rescues Axonal Defects Caused by NMNAT2 Deficiency In Vivo

• Published in: Current biology 2017-03, Vol.27 (6), p.784-794
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Amidohydrolases - genetics; Amidohydrolases - metabolism; Animals; axon degeneration; Axons - pathology; Mice; Mice, Transgenic; NAD; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; neurodegeneration; Nicotinamide-Nucleotide Adenylyltransferase - deficiency; NMN; NMN deamidase; NMNAT; NMNAT2; SARM1; Wallerian degeneration; Wallerian Degeneration - genetics; Wallerian Degeneration - metabolism; WLDs
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2017.01.070

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. •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 Di Stefano et al. show that the NMN-consuming bacterial enzyme NMN deamidase delays degeneration of transected axons in vivo in both mice and zebrafish. It also rescues axonal outgrowth defects and perinatal lethality in mice lacking NMNAT2. These findings support the proposed pro-degenerative effect of NMN accumulation in axons.