Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration
Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration
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DOI：
10.1111/j.1742-4658.2011.08193.x
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发表时间：
2011-08-01
期刊：
影响因子：
5.4
通讯作者：
Coleman, Michael
中科院分区：
文献类型：
--
作者：
Conforti, Laura;Janeckova, Lucie;Coleman, Michael
NAD（+）合成酶NMNAT 1构成神经保护蛋白Wld（S）的大部分序列，其将轴突变性延迟10倍。NMNAT 1活性对于小鼠中的Wld（S）神经保护是必需的但不是足够的，并且Wld（S）N-末端的70个氨基酸（来源于多聚泛素化因子Ube 4 b）增强NMNAT 1对轴突的保护。NMNAT 1活性可以赋予神经保护作用时，重新分配到细胞核外或高度过表达在体外和部分在果蝇。然而，内源性NMNAT 1在正常轴突维持和沃勒变性中的作用尚未阐明。为了解决这个问题，我们通过基因打靶破坏了Nmnat 1基因座。纯合子Nmnat 1基因敲除小鼠不能存活至出生，表明胞核NMNAT亚型不能弥补其损失。杂合Nmnat 1基因敲除小鼠发育正常，未显示自发性神经变性或轴突病理。在这些小鼠中，坐骨神经损伤后的沃勒变性既不加速也不延迟，这与其他内源性NMNAT亚型在沃勒变性中起主要作用的提议一致。
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.