QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, August 16, 2006, 26(33):8484-8491; doi:10.1523/JNEUROSCI.2320-06.2006

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (33) Citing Articles via Google Scholar Google Scholar Articles by Sasaki, Y. Articles by Milbrandt, J. Search for Related Content PubMed PubMed Citation Articles by Sasaki, Y. Articles by Milbrandt, J.

 Previous Article  |  Next Article 

Development/Plasticity/Repair
Stimulation of Nicotinamide Adenine Dinucleotide Biosynthetic Pathways Delays Axonal Degeneration after Axotomy

Yo Sasaki,¹ Toshiyuki Araki,² and Jeffrey Milbrandt¹

¹Departments of Pathology and Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and ²Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

Correspondence should be addressed to Jeffrey Milbrandt, Departments of Pathology and Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110. Email: jmilbrandt{at}wustl.edu

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.

Key words: axotomy; neuropathology; neuroprotection; dorsal root ganglion; nucleus; GFP

---

Received June 1, 2006; revised June 27, 2006; accepted July 3, 2006.

Correspondence should be addressed to Jeffrey Milbrandt, Departments of Pathology and Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110. Email: jmilbrandt{at}wustl.edu

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2006 26: i. [Full Text]  

This article has been cited by other articles:

				S.-P. Lu, M. Kato, and S.-J. Lin Assimilation of Endogenous Nicotinamide Riboside Is Essential for Calorie Restriction-mediated Life Span Extension in Saccharomyces cerevisiae J. Biol. Chem., June 19, 2009; 284(25): 17110 - 17119. [Abstract] [Full Text] [PDF]

				Y. Sasaki, B. P. S. Vohra, R. H. Baloh, and J. Milbrandt Transgenic Mice Expressing the Nmnat1 Protein Manifest Robust Delay in Axonal Degeneration In Vivo J. Neurosci., May 20, 2009; 29(20): 6526 - 6534. [Abstract] [Full Text] [PDF]

				N. Yahata, S. Yuasa, and T. Araki Nicotinamide Mononucleotide Adenylyltransferase Expression in Mitochondrial Matrix Delays Wallerian Degeneration J. Neurosci., May 13, 2009; 29(19): 6276 - 6284. [Abstract] [Full Text] [PDF]

				Y. Sasaki, B. P. S. Vohra, F. E. Lund, and J. Milbrandt Nicotinamide Mononucleotide Adenylyl Transferase-Mediated Axonal Protection Requires Enzymatic Activity But Not Increased Levels of Neuronal Nicotinamide Adenine Dinucleotide J. Neurosci., April 29, 2009; 29(17): 5525 - 5535. [Abstract] [Full Text] [PDF]

				T. J. Tamsett, K. E. Picchione, and A. Bhattacharjee NAD+ Activates KNa Channels in Dorsal Root Ganglion Neurons J. Neurosci., April 22, 2009; 29(16): 5127 - 5134. [Abstract] [Full Text] [PDF]

				M. A. Avery, A. E. Sheehan, K. S. Kerr, J. Wang, and M. R. Freeman WldS requires Nmnat1 enzymatic activity and N16-VCP interactions to suppress Wallerian degeneration J. Cell Biol., February 23, 2009; 184(4): 501 - 513. [Abstract] [Full Text] [PDF]

				B. Beirowski, E. Babetto, J. Gilley, F. Mazzola, L. Conforti, L. Janeckova, G. Magni, R. R. Ribchester, and M. P. Coleman Non-Nuclear WldS Determines Its Neuroprotective Efficacy for Axons and Synapses In Vivo J. Neurosci., January 21, 2009; 29(3): 653 - 668. [Abstract] [Full Text] [PDF]

				C. Press and J. Milbrandt Nmnat Delays Axonal Degeneration Caused by Mitochondrial and Oxidative Stress J. Neurosci., May 7, 2008; 28(19): 4861 - 4871. [Abstract] [Full Text] [PDF]

				P. A. Belenky, T. G. Moga, and C. Brenner Saccharomyces cerevisiae YOR071C Encodes the High Affinity Nicotinamide Riboside Transporter Nrt1 J. Biol. Chem., March 28, 2008; 283(13): 8075 - 8079. [Abstract] [Full Text] [PDF]

				N. Hara, K. Yamada, T. Shibata, H. Osago, T. Hashimoto, and M. Tsuchiya Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells J. Biol. Chem., August 24, 2007; 282(34): 24574 - 24582. [Abstract] [Full Text] [PDF]

				T. M. Wishart, J. M. Paterson, D. M. Short, S. Meredith, K. A. Robertson, C. Sutherland, M. A. Cousin, M. B. Dutia, and T. H. Gillingwater Differential Proteomics Analysis of Synaptic Proteins Identifies Potential Cellular Targets and Protein Mediators of Synaptic Neuroprotection Conferred by the Slow Wallerian Degeneration (Wlds) Gene Mol. Cell. Proteomics, August 1, 2007; 6(8): 1318 - 1330. [Abstract] [Full Text] [PDF]

				L. Kalra and R. Ratan Recent Advances in Stroke Rehabilitation 2006 Stroke, February 1, 2007; 38(2): 235 - 237. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help