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 fusion protein with the nicotinamide adenine dinucleotide (NAD) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Although both Wld(s) 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.
Wang
Jing
J
Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Zhai
Qiwei
Q
Chen
Ying
Y
Lin
Estelle
E
Gu
Wei
W
McBurney
Michael W
MW
He
Zhigang
Z
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D051379:Mice; D009243:NAD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D014855:Wallerian Degeneration / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control
D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C442580:Wld protein, mouse; D009243:NAD; D009536:Niacinamide; D000255:Adenosine Triphosphate; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins