Tracking in the Wlds—The Hunting of the SIRT and the Luring of the Draper

Wallerian degeneration of distal axons after nerve injury is significantly delayed in the Wlds mutant mouse. The Wlds protein is a fusion of nicotinamide mononucleotide adenyltransferase-1 (Nmnat1), an essential enzyme in the biosynthesis pathway of nicotinamide adenine dinucleotide (NAD), with the N-terminal 70 amino acids of the Ube4b ubiquitination assembly factor. The mechanism of Wlds action is still enigmatic, although recent efforts suggest that it is indirect and requires sequences flanking or linking the two fused open reading frames. Three papers in this issue of Neuron now show that Wlds action is conserved in Drosophila and that a critical role of Wlds may be the suppression of axonal self-destruct signals that induce Draper-mediated clearance of damaged axons by glial cells.

[1]  Zhigang He,et al.  Involvement of the Ubiquitin-Proteasome System in the Early Stages of Wallerian Degeneration , 2003, Neuron.

[2]  W. Gu,et al.  A local mechanism mediates NAD-dependent protection of axon degeneration , 2005, The Journal of cell biology.

[3]  V. Perry,et al.  Evidence that the Rate of Wallerian Degeneration is Controlled by a Single Autosomal Dominant Gene , 1990, The European journal of neuroscience.

[4]  Kei Ito,et al.  Essential Role of the Apoptotic Cell Engulfment Genes draper and ced-6 in Programmed Axon Pruning during Drosophila Metamorphosis , 2006, Neuron.

[5]  R. Campenot,et al.  Regulation of Wallerian degeneration and nerve growth factor withdrawal-induced pruning of axons of sympathetic neurons by the proteasome and the MEK/Erk pathway , 2005, Molecular and Cellular Neuroscience.

[6]  T. Nagase,et al.  Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. , 2001, DNA research : an international journal for rapid publication of reports on genes and genomes.

[7]  Izumi Horikawa,et al.  Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. , 2005, Molecular biology of the cell.

[8]  Wilma Dormeyer,et al.  Probing Lysine Acetylation in Proteins , 2005, Molecular & Cellular Proteomics.

[9]  R. Ribchester,et al.  The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves , 2005, BMC Neuroscience.

[10]  Simon C Watkins,et al.  Intra-mitochondrial Poly(ADP-ribosylation) Contributes to NAD+ Depletion and Cell Death Induced by Oxidative Stress* , 2003, The Journal of Biological Chemistry.

[11]  K. Martin,et al.  A Functional Role for Intra-Axonal Protein Synthesis during Axonal Regeneration from Adult Sensory Neurons , 2001, The Journal of Neuroscience.

[12]  Growth Factors,et al.  Minireview , 1999 .

[13]  C. Cotman,et al.  A microfluidic culture platform for CNS axonal injury, regeneration and transport , 2005, Nature Methods.

[14]  Mathias Ziegler,et al.  The new life of a centenarian: signalling functions of NAD(P). , 2004, Trends in biochemical sciences.

[15]  M. Coleman.  Axon degeneration mechanisms: commonality amid diversity , 2005, Nature Reviews Neuroscience.

[16]  R. Ribchester,et al.  The relationship of neuromuscular synapse elimination to synaptic degeneration and pathology: Insights from WldS and other mutant mice , 2003, Journal of neurocytology.

[17]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[18]  M. Freeman,et al.  The Drosophila Cell Corpse Engulfment Receptor Draper Mediates Glial Clearance of Severed Axons , 2006, Neuron.

[19]  V. Perry,et al.  The cellular distribution of the Wlds chimeric protein and its constituent proteins in the CNS , 2005, Neuroscience.

[20]  V. Perry,et al.  The Rate of Wallerian Degeneration in Cultured Neurons from Wild Type and C57BL/WldS Mice Depends on Time in Culture and may be Extended in the Presence of Elevated K+ Levels , 1995, The European journal of neuroscience.

[21]  J. Glass,et al.  NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration , 2007, Cell Death and Differentiation.

[22]  Eric D. Hoopfer,et al.  Wlds Protection Distinguishes Axon Degeneration following Injury from Naturally Occurring Developmental Pruning , 2006, Neuron.

[23]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[24]  H. Su,et al.  Interaction of CED-6/GULP, an Adapter Protein Involved in Engulfment of Apoptotic Cells with CED-1 and CD91/Low Density Lipoprotein Receptor-related Protein (LRP)* , 2002, The Journal of Biological Chemistry.

[25]  Kevin A. Robertson,et al.  The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells. , 2006, Human molecular genetics.

[26]  D. Glanzman,et al.  Axonal Rejoining Inhibits Injury-Induced Long-Term Changes inAplysia Sensory Neurons In Vitro , 2001, The Journal of Neuroscience.

[27]  M. Koltzenburg,et al.  Axoplasmic Importins Enable Retrograde Injury Signaling in Lesioned Nerve , 2003, Neuron.

[28]  R. Ribchester,et al.  The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus. , 2005, Molecular biology of the cell.

[29]  G. Bittner.  Long-term survival of anucleate axons and its implications for nerve regeneration , 1991, Trends in Neurosciences.