The Wlds transgene reduces axon loss in a Charcot-Marie-Tooth disease 1A rat model and nicotinamide delays post-traumatic axonal degeneration
The Wlds transgene reduces axon loss in a Charcot-Marie-Tooth disease 1A rat model and nicotinamide delays post-traumatic axonal degeneration
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DOI：
10.1016/j.nbd.2010.12.006
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发表时间：
2011-04-01
影响因子：
6.1
通讯作者：
Sereda, Michael W.
中科院分区：
文献类型：
--
作者：
Horste, Gerd Meyer Zu;Miesbach, Timo A.;Sereda, Michael W.
腓骨肌萎缩症（Charcot-Marie-Tooth disease，CMT）是最常见的遗传性神经病，其最常见的亚型CMT 1A是由外周髓鞘蛋白22 kDa（peripheral myelin protein of 22 kDa，PMP 22）基因的重复引起的。临床损伤由轴突损失的量确定。自发性小鼠突变型沃勒变性缓慢（Wlds）的轴突在各种类型的损伤后显示出明显减少的变性。通过编码泛素化因子Ube 4 b的N-末端部分和全长烟酰胺单核苷酸腺苷酰转移酶1（Nmnat 1）的嵌合Wlds基因赋予保护。Nmnat 1酶从烟酰胺单核苷酸生成烟酰胺腺嘌呤二核苷酸（NAD）。在此，在腓骨肌萎缩症1A型的Pmp 22转基因动物模型（CMT大鼠）中，Wlds转基因减少了轴突损失和临床损伤，而不改变脱髓鞘。此外，烟酰胺（Nmnat 1酶的底物前体）在急性周围神经损伤的体内模型中短暂延迟了创伤后轴突变性，但程度低于Wlds。相比之下，8周的烟酰胺治疗没有影响CMT大鼠的轴突损失或临床表现。因此，烟酰胺可以部分替代Wlds在急性创伤中的保护作用，但在慢性继发性轴索损伤中不能。未来的研究需要开发CMT 1A的轴突保护疗法，这可能与旨在下调毒性PMP 22过表达的治疗策略相结合。(C)2010年爱思唯尔公司All rights reserved.
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and a duplication of the peripheral myelin protein of 22 kDa (PMP22) gene causes the most frequent subform CMT1A. Clinical impairments are determined by the amount of axonal loss. Axons of the spontaneous mouse mutant Wallerian degeneration slow (Wlds) show markedly reduced degeneration following various types of injuries. Protection is conferred by a chimeric Wlds gene encoding an N-terminal part of ubiquitination factor Ube4b and full length nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1). Nmnat1 enzyme generates nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide. Here, in a Pmp22 transgenic animal model of Charcot-Marie-Tooth disease type 1A (CMT rat), the Wlds transgene reduced axonal loss and clinical impairments without altering demyelination. Furthermore, nicotinamide - substrate precursor of the Nmnat1 enzyme - transiently delayed posttraumatic axonal degeneration in an in vivo model of acute peripheral nerve injury, but to a lower extent than Wlds. In contrast, 8 weeks of nicotinamide treatment did not influence axonal loss or clinical manifestations in the CMT rat. Therefore, nicotinamide can partially substitute for the protective Wlds effect in acute traumatic, but not in chronic secondary axonal injury. Future studies are needed to develop axon protective therapy in CMT1A which may be combined with therapeutic strategies aimed at downregulation of toxic PMP22 overexpression. (C) 2010 Elsevier Inc. All rights reserved.