title: A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.
abstract: NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Di Stefano
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
authors.forename: I
authors.initials: I
authors.lastname: Nascimento-Ferreira
authors.affiliation: Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
authors.forename: G
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: V
authors.initials: V
authors.lastname: Mori
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Gilley
authors.affiliation: SBMS, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
authors.forename: L
authors.initials: L
authors.lastname: Janeckova
authors.affiliation: 1] Jules Stein Eye Institute and Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA 90095, USA [2] Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Vargas
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Worrell
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Loreto
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: J
authors.initials: J
authors.lastname: Tickle
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Patrick
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: J R M
authors.initials: JR
authors.lastname: Webster
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Marangoni
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, Via Gentile III da Varano, Camerino (MC) 62032, Italy.
authors.forename: F M
authors.initials: FM
authors.lastname: Carpi
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, Via Gentile III da Varano, Camerino (MC) 62032, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pucciarelli
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: F
authors.initials: F
authors.lastname: Rossi
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: W
authors.initials: W
authors.lastname: Meng
authors.affiliation: Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sagasti
authors.affiliation: SBMS, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: R R
authors.initials: RR
authors.lastname: Ribchester
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, Via Gentile III da Varano, Camerino (MC) 62032, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Magni
authors.affiliation: The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
authors.forename: M P
authors.initials: MP
authors.lastname: Coleman
authors.affiliation: School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: L
authors.initials: L
authors.lastname: Conforti
mesh_terms: D000581:Amidohydrolases / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001426:Bacterial Proteins / Q000494:pharmacology; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009537:Nicotinamide Mononucleotide / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; D009537:Nicotinamide Mononucleotide; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C579543:Nmnat2 protein, mouse; D000581:Amidohydrolases; C021861:nicotinamidenucleotide amidase