title: NMN Deamidase Delays Wallerian Degeneration and Rescues Axonal Defects Caused by NMNAT2 Deficiency In Vivo.
abstract: 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.
authors.affiliation: School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK; Clinical Neuroscience, UCL Institute of Neurology, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Di Stefano
authors.affiliation: School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Loreto
authors.affiliation: Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Orsomando
authors.affiliation: Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mori
authors.affiliation: Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zamporlini
authors.affiliation: Cancer Biology, School of Cancer and Stem Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hulse
authors.affiliation: School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Webster
authors.affiliation: School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Donaldson
authors.affiliation: School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Gering
authors.affiliation: Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Raffaelli
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; The Babraham Institute, Babraham, Cambridge CB22 3AT, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; The Babraham Institute, Babraham, Cambridge CB22 3AT, UK. Electronic address: jg792@cam.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.affiliation: School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK. Electronic address: laura.conforti@hotmail.co.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
mesh_terms: D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000172:deficiency*; D014855:Wallerian Degeneration / Q000235:genetics* / Q000378:metabolism
chemical_list: D009612:Nicotinamide-Nucleotide Adenylyltransferase; C579543:Nmnat2 protein, mouse; D000581:Amidohydrolases; C021861:nicotinamidenucleotide amidase
keywords: NAD; NMN; NMN deamidase; NMNAT; NMNAT2; SARM1; WLD(s); Wallerian degeneration; axon degeneration; neurodegeneration