A Local Mechanism Mediates NAD-Dependent Protection of Axon Degeneration

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 f...

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Bibliographic Details
Published in:The Journal of cell biology 2005-08, Vol.170 (3), p.349-355
Main Authors: Wanq, Jinq, Zhai, Qiwei, Chen, Ying, Lin, Estelle, Gu, Wei, McBurney, Michael W., He, Zhigang
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Axons
Axons - metabolism
Axons - pathology
Axotomy
Cell culture
Cells, Cultured
Cellular biology
Computer software
Enzymes
Ganglia
Mice
NAD - genetics
NAD - metabolism
NAD - physiology
Nerve Tissue Proteins - metabolism
Neurons
Neuroscience
Niacinamide - metabolism
Nicotinamide-Nucleotide Adenylyltransferase - genetics
Nicotinamide-Nucleotide Adenylyltransferase - metabolism
Protective effects
Quantification
Rats
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Sirtuin 1
Sirtuins - metabolism
Statistical analysis
Wallerian degeneration
Wallerian Degeneration - genetics
Wallerian Degeneration - pathology
Wallerian Degeneration - prevention & control
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Summary: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 Nmnatl - 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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200504028