Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance
Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance
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DOI：
10.1523/jneurosci.3007-09.2009
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发表时间：
2009-09-16
影响因子：
5.3
通讯作者：
Glynn, Paul
中科院分区：
文献类型：
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作者：
Read, David J.;Li, Yong;Glynn, Paul
神经病靶标酯酶 (NTE) 存在于神经元中，可使主要膜磷脂磷脂酰胆碱 (PtdCho) 脱酰。 NTE 基因突变或神经病性有机磷酸酯（NTE 化学抑制剂）中毒会导致人类长脊髓轴突远端变性。然而，在具有NTE缺陷神经组织的nesincre:NTEfl/fl小鼠中尚未报道类似的神经病理学变化。此外，在 NTE 缺陷的脊椎动物中尚未检测到 PtdCho 稳态的改变。在这里，我们描述了与 3 周龄的 nestin-cre:NTEfl/fl 小鼠和成年 C57BL/6J 小鼠在急性给药神经性有机磷酸盐后类似的最长脊髓轴突的远端变性：在两组中，早期退行性病变随后出现由积累的轴浆物质组成的肿胀。在急性给予有机磷酸盐的小鼠中，最长的脊髓感觉轴突束中的损伤数量在几天内就达到了最大，并且在此之前神经 PtdCho 出现了短暂的升高。在 nestin-cre: NTEfl/fl 小鼠中，PtdCho 在数月内持续升高，伴随着感觉和运动脊髓束中轴突的进行性退化和大量肿胀以及后肢功能障碍的增加。轴突病变分布与遗传性痉挛性截瘫（HSP）非常相似。 HSP 中膜运输缺陷的重要性以及 NTE 与内质网的关联（构成性分泌途径和神经元物质转运至轴突的起点）促使人们研究 NTE 在分泌中的作用。培养的 NTE 缺陷神经元表现出适度的分泌受损，与神经元活力和体内损伤一致，最初仅限于最长轴突的远端部分。
The enzyme neuropathy target esterase (NTE) is present in neurons and deacylates the major membrane phospholipid, phosphatidylcholine (PtdCho). Mutation of the NTE gene or poisoning by neuropathic organophosphates-chemical inhibitors of NTE-causes distal degeneration of long spinal axons in humans. However, analogous neuropathological changes have not been reported in nestincre:NTEfl/fl mice with NTE-deficient neural tissue. Furthermore, altered PtdCho homeostasis has not been detected in NTE-deficient vertebrates. Here, we describe distal degeneration of the longest spinal axons in similar to 3-week-old nestin-cre:NTEfl/fl mice and in adult C57BL/6J mice after acute dosing with a neuropathic organophosphate: in both groups early degenerative lesions were followed by swellings comprising accumulated axoplasmic material. In mice dosed acutely with organophosphate, maximal numbers of lesions, in the longest spinal sensory axon tract, were attained within days and were preceded by a transient rise in neural PtdCho. In nestin-cre: NTEfl/fl mice, sustained elevation of PtdCho over many months was accompanied by progressive degeneration and massive swelling of axons in sensory and motor spinal tracts and by increasing hindlimb dysfunction. Axonal lesion distribution closely resembled that in hereditary spastic paraplegia (HSP). The importance of defective membrane trafficking in HSP and the association of NTE with the endoplasmic reticulum-the starting point for the constitutive secretory pathway and transport of neuronal materials into axons prompted investigation for a role of NTE in secretion. Cultured NTE-deficient neurons displayed modestly impaired secretion, consistent with neuronal viability and damage in vivo initially restricted to distal parts of the longest axons.