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The Journal of Neuroscience, April 29, 2009, 29(17):5525-5535; doi:10.1523/JNEUROSCI.5469-08.2009

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Development/Plasticity/Repair
Nicotinamide Mononucleotide Adenylyl Transferase-Mediated Axonal Protection Requires Enzymatic Activity But Not Increased Levels of Neuronal Nicotinamide Adenine Dinucleotide

Yo Sasaki,^1 * Bhupinder P. S. Vohra,^1 * Frances E. Lund,⁴ and Jeffrey Milbrandt^1,2,3

Departments of ¹Pathology and Immunology and ²Neurology and ³Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁴Division of Allergy, Immunology, and Rheumatology, University of Rochester, Rochester, New York 14642

Correspondence should be addressed to Jeffrey Milbrandt at the above address. Email: jmilbrandt{at}wustl.edu

Axonal degeneration is a hallmark of many neurological disorders. Studies in animal models of neurodegenerative diseases indicate that axonal degeneration is an early event in the disease process, and delaying this process can lead to decreased progression of the disease and survival extension. Overexpression of the Wallerian degeneration slow (Wld^s) protein can delay axonal degeneration initiated via axotomy, chemotherapeutic agents, or genetic mutations. The Wld^s protein consists of the N-terminal portion of the ubiquitination factor Ube4b fused to the nicotinamide adenine dinucleotide (NAD⁺) biosynthetic enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1). We previously showed that the Nmnat1 portion of this fusion protein was the critical moiety for Wld^s-mediated axonal protection. Here, we describe the development of an automated quantitative assay for assessing axonal degeneration. This method successfully showed that Nmnat1 enzymatic activity is important for axonal protection as mutants with reduced enzymatic activity lacked axon protective activity. We also found that Nmnat enzymes with diverse sequences and structures from various species, including Drosophila melanogaster, Saccharomyces cerevisiae, and archaebacterium Methanocaldococcus jannaschii, which encodes a protein with no homology to eukaryotic Nmnat enzymes, all mediate robust axonal protection after axotomy. Besides the importance of Nmnat enzymatic activity, we did not observe changes in the steady-state NAD⁺ level, and we found that inhibition of nicotinamide phosphoribosyltransferase (Nampt), which synthesizes substrate for Nmnat in mammalian cells, did not affect the protective activity of Nmnat1. These results provide the possibility of a role for new Nmnat enzymatic activity in axonal protection in addition to NAD⁺ synthesis.

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Received Nov. 12, 2008; revised Jan. 7, 2009; accepted Jan. 26, 2009.

Correspondence should be addressed to Jeffrey Milbrandt at the above address. Email: jmilbrandt{at}wustl.edu

This article has been cited by other articles:

				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]

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