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Cell Death Differ. 2015 May;22(5):731-42. doi: 10.1038/cdd.2014.164. Epub 2014 Oct 17.

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

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School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
SBMS, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
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.
School of Biosciences and Biotechnology, University of Camerino, Via Gentile III da Varano, Camerino (MC) 62032, Italy.
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.


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.

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