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Published online 25 July 2005. doi:10.1083/jcb.200504028
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 3, 349-355
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A local mechanism mediates NAD-dependent protection of axon degeneration



Jing Wang1, Qiwei Zhai1,2, Ying Chen1, Estelle Lin1, Wei Gu3, Michael W. McBurney4, and Zhigang He1

1 Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, MA 02115
2 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
3 Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
4 Ottawa Regional Cancer Centre and Department of Medicine, University of Ottawa, Ontario K1H 1C4, Canada

Correspondence to Zhigang He: zhigang.he{at}childrens.harvard.edu; or Qiwei Zhai: qwzhai{at}sibs.ac.cn


Abstract

Axon degeneration occurs frequently in neurodegenerative diseases and peripheral neuropathies. Important insight into the mechanisms of axon degeneration arose from findings that the degeneration of transected axons is delayed in Wallerian degeneration slow (Wlds) mice with the overexpression of a fusion protein with the nicotinamide adenine dinucleotide (NAD) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Although both Wlds and Nmnat1 themselves are functional in preventing axon degeneration in neuronal cultures, the underlying mechanism for Nmnat1- and NAD-mediated axon protection remains largely unclear. We demonstrate that NAD levels decrease in degenerating axons and that preventing this axonal NAD decline efficiently protects axons from degeneration. In support of a local protective mechanism, we show that the degeneration of axonal segments that have been separated from their soma could be prevented by the exogenous application of NAD or its precursor nicotinamide. Furthermore, we provide evidence that such Nmnat1/NAD-mediated protection is primarily mediated by their effects on local bioenergetics. Together, our results suggest a novel molecular pathway for axon degeneration.

Abbreviations used in this paper: AMPK, AMP-activated protein kinase; DRG, dorsal root ganglion; HSV, Herpes simplex virus; NAD, nicotinamide adenine dinucleotide; Nmnat1, nicotinamide mononucleotide adenylyltransferase; Wlds, Wallerian degeneration slow.


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