Stimulation of Nicotinamide Adenine Dinucleotide Biosynthetic Pathways Delays Axonal Degeneration after Axotomy
Open accessAbstract
Axonal degeneration occurs in many neurodegenerative diseases and after traumatic injury and is a self-destructive program independent from programmed cell death. Previous studies demonstrated that overexpression of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) or exogenous application of nicotinamide adenine dinucleotide (NAD) can protect axons of cultured dorsal root ganglion (DRG) neurons from degeneration caused by mechanical or neurotoxic injury. In mammalian cells, NAD can be synthesized from multiple precursors, including tryptophan, nicotinic acid, nicotinamide, and nicotinamide riboside (NmR), via multiple enzymatic steps. To determine whether other components of these NAD biosynthetic pathways are capable of delaying axonal degeneration, we overexpressed each of the enzymes involved in each pathway and/or exogenously administered their respective substrates in DRG cultures and assessed their capacity to protect axons after axotomy. Among the enzymes tested, Nmnat1 had the strongest protective effects, whereas nicotinamide phosphoribosyl transferase and nicotinic acid phosphoribosyl transferase showed moderate protective activity in the presence of their substrates. Strong axonal protection was also provided by Nmnat3, which is predominantly located in mitochondria, and an Nmnat1 mutant localized to the cytoplasm, indicating that the subcellular location of NAD production is not crucial for protective activity. In addition, we showed that exogenous application of the NAD precursors that are the substrates of these enzymes, including nicotinic acid mononucleotide, nicotinamide mononucleotide, and NmR, can also delay axonal degeneration. These results indicate that stimulation of NAD biosynthetic pathways via a variety of interventions may be useful in preventing or delaying axonal degeneration.
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The induction of NRK2 in response to cellular damage or stress suggests the existence of a demand for circulating NR.
“In addition, the induction of NRK2 in response to cellular damage or stress32 suggests the existence of a demand for circulating NR.”
From NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells (2016) · cites this paper as [32]
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Cites
Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration
Araki, T., Sasaki, Y., & Milbrandt, J. (2004) · Science · doi:10.1126/science.1098014 · Cited by 1,060 · see citing works
Self-citationRevollo, J. R., Grimm, A. A., & Imai, S.-I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408388200 · Cited by 1,010 · see citing works
Axon degeneration mechanisms: Commonality amid diversity
Coleman, M. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1788 · Cited by 819 · see citing works
Bieganowski, P., & Brenner, C. (2004) · Cell · doi:10.1016/s0092-8674(04)00416-7 · Cited by 750 · see citing works
Axonal Self-Destruction and Neurodegeneration
Raff, M., Whitmore, A., & Finn, J. (2002) · Science · doi:10.1126/science.1068613 · Cited by 670 · see citing works
Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve
Lunn, E. R., Perry, V. H., Brown, M. C., Rosen, H., & Gordon, S. (1989) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1989.tb00771.x · Cited by 646 · see citing works
Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene
Mack, T. G. A., Reiner, M., Beirowski, B., Mi, W., Emanuelli, M., Wagner, D., Thomson, D., Gillingwater, T., Court, F., Conforti, L., et al. (2001) · Nature Neuroscience · doi:10.1038/nn770 · Cited by 611 · see citing works
The Drosophila Cell Corpse Engulfment Receptor Draper Mediates Glial Clearance of Severed Axons
MacDonald, J. M., Beach, M. G., Porpiglia, E., Sheehan, A. E., Watts, R. J., & Freeman, M. R. (2006) · Neuron · doi:10.1016/j.neuron.2006.04.028 · Cited by 523 · see citing works
A local mechanism mediates NAD-dependent protection of axon degeneration
Wang, J., Zhai, Q., Chen, Y., Lin, E., Gu, W., McBurney, M. W., & He, Z. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200504028 · Cited by 352 · see citing works
Conforti, L., Tarlton, A., Mack, T. G. A., Mi, W., Buckmaster, E. A., Wagner, D., Perry, V. H., & Coleman, M. P. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.21.11377 · Cited by 251 · see citing works
Conforti, L., Fang, G., Beirowski, B., Wang, M. S., Sorci, L., Asress, S., Adalbert, R., Silva, A., Bridge, K., Huang, X. P., et al. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401944 · Cited by 136 · see citing works
Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., & Zhang, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300073200 · Cited by 136 · see citing works
Very Slow Retrograde and Wallerian Degeneration in the CNS of C57BL/Ola Mice
Perry, V. H., Brown, M. C., & Lunn, E. R. (1991) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1991.tb00815.x · Cited by 133 · see citing works
Identification of a novel human nicotinamide mononucleotide adenylyltransferase
Raffaelli, N., Sorci, L., Amici, A., Emanuelli, M., Mazzola, F., & Magni, G. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02285-4 · Cited by 127 · see citing works
Wang, M.-S., Fang, G., Culver, D. G., Davis, A. A., Rich, M., & Glass, J. (2001) · Annals of Neurology · doi:10.1002/ana.10039 · Cited by 105 · see citing works
RAMPAGE: Promoter Activity Profiling by Paired-End Sequencing of 5′-Complete cDNAs
Batut, P. J., & Gingeras, T. (2013) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb25b11s104 · Cited by 79 · see citing works
Identification of Genes Induced in Peripheral Nerve after Injury
Araki, T., Nagarajan, R., & Milbrandt, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104271200 · Cited by 76 · see citing works
Self-citationMolecular Identification of Human Glutamine- and Ammonia-dependent NAD Synthetases
Hara, N., Yamada, K., Terashima, M., Osago, H., Shimoyama, M., & Tsuchiya, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209203200 · Cited by 74 · see citing works
Laser, H., Conforti, L., Morreale, G., Mack, T. G. A., Heyer, M., Haley, J. E., Wishart, T. M., Beirowski, B., Walker, S. A., Haase, G., et al. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-04-0375 · Cited by 61 · see citing works
Tong, J. X., Eichler, M. E., & Rich, K. M. (1996) · Experimental Neurology · doi:10.1006/exnr.1996.0045 · Cited by 50 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Ausubel FM (2001) Current protocols in molecular biology, Vol 1, Chap 8. New York: Wiley.
Cited by
Sorted by citations
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
Clinical progression in Parkinson disease and the neurobiology of axons
Cheng, H., Ulane, C. M., & Burke, R. E. (2010) · Annals of Neurology · doi:10.1002/ana.21995 · Cited by 1,012 · see citing works
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways
Houtkooper, R. H., Cantó, C., Wanders, R. J., & Auwerx, J. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0026 · Cited by 899 · see citing works
Bogan, K. L., & Brenner, C. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155443 · Cited by 707 · see citing works
NAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627 · see citing works
SARM1 activation triggers axon degeneration locally via NAD <sup>+</sup> destruction
Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A., & Milbrandt, J. (2015) · Science · doi:10.1126/science.1258366 · Cited by 593 · see citing works
Self-citationEndogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons
Gilley, J., & Coleman, M. P. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000300 · Cited by 472 · see citing works
Belenky, P., Racette, F. G., Bogan, K. L., McClure, J. M., Smith, J. S., & Brenner, C. (2007) · Cell · doi:10.1016/j.cell.2007.03.024 · Cited by 411 · see citing works
NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells
Ratajczak, J., Joffraud, M., Trammell, S. A. J., Ras, R., Canela, N., Boutant, M., Kulkarni, S. S., Rodrigues, M., Redpath, P., Migaud, M. E., et al. (2016) · Nature Communications · doi:10.1038/ncomms13103 · Cited by 378 · see citing works
“In addition, the induction of NRK2 in response to cellular damage or stress 32 suggests the existence of a demand for circulating NR.”
Repairing mitochondrial dysfunction in disease
Sorrentino, V., Menzies, K. J., & Auwerx, J. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104908 · Cited by 337 · see citing works
Protein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice
Trammell, S. A. J., Weidemann, B. J., Chadda, A., Yorek, M. S., Holmes, A., Coppey, L. J., Obrosov, A., Kardon, R. H., Yorek, M. A., & Brenner, C. (2016) · Scientific Reports · doi:10.1038/srep26933 · Cited by 301 · see citing works
Brown, K. D., Maqsood, S., Huang, J.-Y., Pan, Y., Harkcom, W., Li, W., Sauve, A., Verdin, E., & Jaffrey, S. R. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.11.003 · Cited by 277 · see citing works
Liu, D., Pitta, M., Jiang, H., Lee, J.-H., Zhang, G., Chen, X., Kawamoto, E. M., & Mattson, M. P. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.020 · Cited by 238 · see citing works
Hara, N., Yamada, K., Shibata, T., Osago, H., Hashimoto, T., & Tsuchiya, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610357200 · Cited by 205 · see citing works
Conze, D., Brenner, C., & Kruger, C. L. (2019) · Scientific Reports · doi:10.1038/s41598-019-46120-z · Cited by 210 · see citing works
NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion
Sasaki, Y., Nakagawa, T., Mao, X., DiAntonio, A., & Milbrandt, J. (2016) · eLife · doi:10.7554/elife.19749 · Cited by 192 · see citing works
Self-citationYahata, N., Yuasa, S., & Araki, T. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4304-08.2009 · Cited by 154 · see citing works
“We showed in a previous report that lentiviral NMNAT1 overexpression in primary cultured neurons results in the axonal protection phenotype in the Wallerian degeneration model in vitro (Araki et al., 2004; Sasaki et al., 2006).”
BackgroundMethodInfluentialSelf-citationLoreto, A., Hill, C. S., Hewitt, V. L., Orsomando, G., Angeletti, C., Gilley, J., Lucci, C., Sanchez-Martinez, A., Whitworth, A. J., Conforti, L., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104678 · Cited by 131 · see citing works
Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress
Press, C., & Milbrandt, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0525-08.2008 · Cited by 137 · see citing works
“…axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury (Gillingwater and Ribchester, 2001; Wang et al., 2001a,b; Ferri et al., 2003; Samsam et al., 2003; Araki et al., 2004; Gillingwater et al., 2004; Mi et al., 2005; Sasaki et al., 2006; Zhai et al., 2006).”
BackgroundMethodResultInfluentialSelf-citationAxonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration
Kitaoka, Y., Munemasa, Y., Kojima, K., Hirano, A., Ueno, S., & Takagi, H. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.391 · Cited by 108 · see citing works
Liu, H.-W., Smith, C. B., Schmidt, M. S., Cambronne, X. A., Cohen, M. S., Migaud, M. E., Brenner, C., & Goodman, R. H. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1809392115 · Cited by 105 · see citing works
NMNATs, evolutionarily conserved neuronal maintenance factors
Ali, Y. O., Li-Kroeger, D., Bellen, H. J., Zhai, R. G., & Lu, H.-C. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.07.002 · Cited by 91 · see citing works
Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity
Yan, T., Feng, Y., Zheng, J., Ge, X., Zhang, Y., Wu, D., Zhao, J., & Zhai, Q. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2009.09.007 · Cited by 92 · see citing works
Mayer, P. R., Huang, N., Dewey, C. M., Dries, D. R., Zhang, H., & Yu, G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178913 · Cited by 82 · see citing works
Saccharomyces cerevisiae YOR071C Encodes the High Affinity Nicotinamide Riboside Transporter Nrt1
Belenky, P. A., Moga, T. G., & Brenner, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.c800021200 · Cited by 78 · see citing works
Lu, S.-P., Kato, M., & Lin, S.-J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.004010 · Cited by 75 · see citing works
Ruggieri, S., Orsomando, G., Sorci, L., & Raffaelli, N. (2015) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2015.02.021 · Cited by 71 · see citing works
Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Hikosaka, K., Yaku, K., Okabe, K., & Nakagawa, T. (2021) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1637504 · Cited by 62 · see citing works
Takaso, Y., Noda, M., Hattori, T., Roboon, J., Hatano, M., Sugimoto, H., Brenner, C., Yamamoto, Y., Okamoto, H., Higashida, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73984-3 · Cited by 17 · see citing works
- Authors
- Sasaki, Y., Araki, T., & Milbrandt, J.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-08-16
- Volume
- 26
- Issue
- 33
- Pages
- 8484-8491
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674352
- OpenAlex
- W2038084692
- Cited by
- 269
- References
- 20
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 12 · 2022: 13 · 2021: 10 · 2020: 23 · 2019: 15 · 2018: 12 · 2017: 10 · 2016: 16 · 2015: 16 · 2014: 25 · 2013: 14 · 2012: 14
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- Hope Center for Neurological Disorders
- National Institutes of Health (5r21ns049087-02, AG13730)
- National Institute on Aging (AG 13730)
- National Institute of Neurological Disorders and Stroke (NS049087, NS39358, R01NS039358)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- axonal degeneration, axotomy, NAD biosynthesis, NMNAT1, NMNAT3, visfatin, nicotinamide riboside, nicotinamide mononucleotide, nicotinic acid mononucleotide, dorsal root ganglion neurons, axonal protection, subcellular localization, neuroprotection
- MeSH terms
- Animals, Axons, Cell Line, Denervation, Enzyme Precursors, Enzymes, Ganglia, Spinal, Humans, Male, NAD, Nerve Degeneration, Neurons, Nicotinamide-Nucleotide Adenylyltransferase, Postoperative Period, Sciatic Nerve, Time Factors, Rats, Sprague-Dawley, Axotomy, Rats
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