The WldS protein protects against axonal degeneration:: A model of gene therapy for peripheral neuropathy
The WldS protein protects against axonal degeneration:: A model of gene therapy for peripheral neuropathy
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DOI：
10.1002/ana.10039
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发表时间：
2001-12-01
影响因子：
11.2
通讯作者：
Glass, JD
中科院分区：
文献类型：
--
作者：
Wang, MS;Fang, GF;Glass, JD
Wld(S)小鼠是一种自发突变体，其表型特征是横断神经的延迟变性（慢沃勒氏变性）。分子遗传分析在这种动物身上发现了一个突变，该突变编码了在Wld(S)小鼠脑组织中表达的一种独特蛋白质。我们询问Wld(S)表型，除了延缓轴突切开术后的轴突变性外，是否可能对中毒性神经病提供神经保护。在背根神经节（DRG）培养中，短暂暴露于长春新碱的Wld(S)神经突不仅抵抗轴突变性，而且在毒素退出后恢复生长。野生型小鼠的神经突迅速死亡且不恢复。为了证明鉴定的突变及其蛋白产物是导致Wld(S)表型的原因，我们使用腺病毒基因转移系统将Wld(S)传递到大鼠DRG神经元。表达Wld(S)蛋白的大鼠神经元对长春新碱诱导的轴突变性具有抗性，证实了所鉴定的基因突变的功能意义。这些数据提供了证据，表明Wld(S)蛋白可以对长春新碱性神经病和其他可能以轴突变性为特征的疾病具有神经保护作用。此外，将该基因传递到野生型细胞中可以转移Wld(S)表型，为周围神经病变的“基因治疗”提供了可能。
The Wld(S) mouse is a spontaneous mutant that is characterized by the phenotype of delayed degeneration of transected nerves (slow Wallerian degeneration). Molecular genetic analysis identified a mutation in this animal that codes for a unique protein expressed in brain tissue of Wld(S) mice. We asked whether the Wld(S) phenotype, in addition to delaying axonal degeneration after axotomy, might provide neuroprotection against toxic neuropathy. In dorsal root ganglia (DRG) cultures, neurites from Wld(S) transiently exposed to vincristine not only resisted axonal degeneration but resumed growth after withdrawal of the toxin. Neurites from wild type mice died rapidly and did not recover. To prove that the identified mutation and its protein product are responsible for the Wld(S) phenotype, we used an adenoviral gene transfer system to deliver the Wld(S) to rat DRG neurons. Rat neurons expressing the Wld(S) protein were resistant to vincristine-induced axonal degeneration, confirming the functional significance of the identified gene mutation. These data provide evidence that the Wld(S) protein can be neuroprotective against vincristine neuropathy, and possibly other disorders characterized by axonal degeneration. In addition, delivery of this gene to wild type cells can transfer the Wld(S) phenotype, providing the possibility of "gene therapy" for peripheral neuropathy.