title: Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration.
abstract: NAD(+) synthesizing enzyme NMNAT1 constitutes most of the sequence of neuroprotective protein Wld(S), which delays axon degeneration by 10-fold. NMNAT1 activity is necessary but not sufficient for Wld(S) neuroprotection in mice and 70 amino acids at the N-terminus of Wld(S), 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.
authors: The Babraham Institute, Cambridge, UK. laura.conforti@nottingham.ac.uk
authors: Laura
authors: L
authors: Conforti
authors: Lucie
authors: L
authors: Janeckova
authors: Diana
authors: D
authors: Wagner
authors: Francesca
authors: F
authors: Mazzola
authors: Lucia
authors: L
authors: Cialabrini
authors: Michele
authors: M
authors: Di Stefano
authors: Giuseppe
authors: G
authors: Orsomando
authors: Giulio
authors: G
authors: Magni
authors: Caterina
authors: C
authors: Bendotti
authors: Neil
authors: N
authors: Smyth
authors: Michael
authors: M
authors: Coleman