Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.
Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/WldS mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.
Mack
T G
TG
Center for Molecular Medicine (ZMMK) and Institute for Genetics, University of Cologne, Zuelpicher Strasse 47, D-50674 Cologne, Germany.
Reiner
M
M
Beirowski
B
B
Mi
W
W
Emanuelli
M
M
Wagner
D
D
Thomson
D
D
Gillingwater
T
T
Court
F
F
Conforti
L
L
Fernando
F S
FS
Tarlton
A
A
Andressen
C
C
Addicks
K
K
Magni
G
G
Ribchester
R R
RR
Perry
V H
VH
Coleman
M P
MP
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D001483:Base Sequence / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002470:Cell Survival / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development / Q000294:innervation / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009420:Nervous System / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000648:ultrastructure; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics; D013572:Synaptic Vesicles / Q000378:metabolism; D020196:Trauma, Nervous System; D044763:Ubiquitin-Conjugating Enzymes; D014855:Wallerian Degeneration / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
D005656:Fungal Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C442580:Wld protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C114683:UFD2 protein, S cerevisiae