Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration

Laura Conforti, Lucie Janeckova, Diana Wagner, Francesca Mazzola, Lucia Cialabrini, Michele Di Stefano, Giuseppe Orsomando, Giulio Magni, Caterina Bendotti, Neil Smyth, Michael Coleman

Research output: Contribution to journalArticle

Abstract

NAD+ synthesizing enzyme NMNAT1 constitutes most of the sequence of neuroprotective protein WldS, which delays axon degeneration by 10-fold. NMNAT1 activity is necessary but not sufficient for WldS neuroprotection in mice and 70 amino acids at the N-terminus of WldS, derived from polyubiquitination factor Ube4b, enhance axon protection by NMNAT1. NMNAT1 activity can confer neuroprotection when redistributed outside the nucleus or when highly overexpressed in vitro and partially in Drosophila. However, the role of endogenous NMNAT1 in normal axon maintenance and in Wallerian degeneration has not been elucidated yet. To address this question we disrupted the Nmnat1 locus by gene targeting. Homozygous Nmnat1 knockout mice do not survive to birth, indicating that extranuclear NMNAT isoforms cannot compensate for its loss. Heterozygous Nmnat1 knockout mice develop normally and do not show spontaneous neurodegeneration or axon pathology. Wallerian degeneration after sciatic nerve lesion is neither accelerated nor delayed in these mice, consistent with the proposal that other endogenous NMNAT isoforms play a principal role in Wallerian degeneration.

Original languageEnglish
Pages (from-to)2666-2679
Number of pages14
JournalFEBS Journal
Volume278
Issue number15
DOIs
Publication statusPublished - Aug 2011

Keywords

  • axon
  • Cre-loxP knockout
  • NAD(P)
  • NMNAT
  • Wallerian degeneration

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Conforti, L., Janeckova, L., Wagner, D., Mazzola, F., Cialabrini, L., Di Stefano, M., Orsomando, G., Magni, G., Bendotti, C., Smyth, N., & Coleman, M. (2011). Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration. FEBS Journal, 278(15), 2666-2679. https://doi.org/10.1111/j.1742-4658.2011.08193.x