Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.
Axonal degeneration is an active program of self-destruction that is observed in many physiological and pathological settings. In Wallerian degeneration slow (wlds) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wlds) composed of the ubiquitin assembly protein Ufd2a and the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme Nmnat1. We demonstrate that increased Nmnat activity is responsible for the axon-sparing activity of the Wlds protein. Furthermore, we demonstrate that SIRT1, a mammalian ortholog of Sir2, is the downstream effector of increased Nmnat activity that leads to axonal protection. These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration.
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Toshiyuki
T
Araki
Yo
Y
Sasaki
Jeffrey
J
Milbrandt
D016475:3T3 Cells; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019771:Axotomy; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000502:physiology; D051379:Mice; D009154:Mutation; D009243:NAD / Q000096:biosynthesis* / Q000494:pharmacology; D009284:Naphthols / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D014855:Wallerian Degeneration / Q000378:metabolism / Q000503:physiopathology*
D001549:Benzamides; D009243:NAD; D009284:Naphthols; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D034741:RNA, Small Interfering; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins; D013267:Stilbenes; D044767:Ubiquitin-Protein Ligases; D014750:Vincristine; C442580:Wld protein, mouse; C439060:sirtinol; C025160:3-aminobenzamide; C471292:Ube4b protein, mouse; C470545:Sirt1 protein, mouse; C510972:Nmnat1 protein, mouse