Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene

被引:491
作者
Mack, TGA
Reiner, M
Beirowski, B
Mi, WQ
Emanuelli, M
Wagner, D
Thomson, D
Gillingwater, T
Court, F
Conforti, L
Fernando, FS
Tarlton, A
Andressen, C
Addicks, K
Magni, G
Ribchester, RR
Perry, VH
Coleman, MP
机构
[1] Univ Cologne, Ctr Mol Med, D-50674 Cologne, Germany
[2] Univ Cologne, Inst Genet, D-50674 Cologne, Germany
[3] Univ Cologne, Dept Anat 1, D-50931 Cologne, Germany
[4] Univ Ancona, Inst Biochem, I-60131 Ancona, Italy
[5] Univ Edinburgh, Dept Neurosci, Edinburgh EH8 9JZ, Midlothian, Scotland
[6] Mario Negri Inst Pharmacol Res, Mol Neurobiol Lab, I-20157 Milan, Italy
[7] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England
[8] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England
[9] Univ Southampton, Sch Biol Sci, Southampton SO16 7PX, Hants, England
基金
英国惠康基金;
关键词
D O I
10.1038/nn770
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/Wld(S) 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 Wld(S) tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.
引用
收藏
页码:1199 / 1206
页数:8
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