Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.
Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.
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DOI：
10.1371/journal.pone.0087526
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kretzschmar D
中科院分区：
文献类型：
--
作者：
Wentzell JS;Cassar M;Kretzschmar D
有机磷诱导的迟发性神经病(OPIDN)是一种沃勒型轴索病变，发生在暴露于某些有机磷(OP)的几周后。已有研究表明，OPs可与神经病变靶标酯酶(NTE)结合，从而抑制其酶活性。然而，只有也引起所谓的老化反应的OP才会引起OPIDN。这个反应导致一个侧基从结合的OP释放并可能转移到NTE，有人认为这导致了NTE未知的毒性作用。为了进一步研究衰老OPS的机制，我们使用了果蝇，它表达了一个功能保守的NTE同源基因，名为Swiss Cheese(SWS)。用有机磷化合物三邻甲酚磷酸盐(TOCP)治疗果蝇，在暴露两周后会导致行为障碍和神经退化，症状与其他模型中观察到的延迟效应相似。此外，我们发现初级神经元在治疗后一小时内显示出轴突变性的迹象。令人惊讶的是，增加SWS的水平，从而在暴露后提高其酶活性，并没有改善这些表型。相反，降低SWS水平可防止TOCP诱导的变性和行为缺陷，但不影响细胞培养中观察到的轴突病变。除了作为磷脂酶的酶活性外，SWS还作为调节PKA亚基，结合和抑制C3催化亚基。测量TOCP处理的果蝇的PKA活性显示，处理的大鼠海马神经元中的PKA活性显著降低。表达额外PKA-C3的果蝇不受TOCP暴露引起的行为和退化表型的影响，而初级神经元则没有。此外，敲除PKA-C3可引起与TOCP处理相似的行为和退化表型。因此，我们提出了一个模型，在该模型中，OP修饰的SWS不能释放PKA-C3，并且由此导致的PKA-C3活性的丧失在OPIDN延迟症状的形成中起关键作用，而在急性毒性中不起关键作用。
Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic function of NTE. To further investigate the mechanisms of aging OPs, we used Drosophila, which expresses a functionally conserved orthologue of NTE named Swiss Cheese (SWS). Treating flies with the organophosporous compound tri-ortho-cresyl phosphate (TOCP) resulted in behavioral deficits and neurodegeneration two weeks after exposure, symptoms similar to the delayed effects observed in other models. In addition, we found that primary neurons showed signs of axonal degeneration within an hour after treatment. Surprisingly, increasing the levels of SWS, and thereby its enzymatic activity after exposure, did not ameliorate these phenotypes. In contrast, reducing SWS levels protected from TOCP-induced degeneration and behavioral deficits but did not affect the axonopathy observed in cell culture. Besides its enzymatic activity as a phospholipase, SWS also acts as regulatory PKA subunit, binding and inhibiting the C3 catalytic subunit. Measuring PKA activity in TOCP treated flies revealed a significant decrease that was also confirmed in treated rat hippocampal neurons. Flies expressing additional PKA-C3 were protected from the behavioral and degenerative phenotypes caused by TOCP exposure whereas primary neurons were not. In addition, knocking-down PKA-C3 caused similar behavioral and degenerative phenotypes as TOCP treatment. We therefore propose a model in which OP-modified SWS cannot release PKA-C3 and that the resulting loss of PKA-C3 activity plays a crucial role in developing the delayed symptoms of OPIDN but not in the acute toxicity.
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DOI：
10.1073/pnas.0702726104
发表时间：
2007-05-15
影响因子：
11.1
作者：
Ja, William W.;Carvalho, Gil B.;Benzer, Seymour
通讯作者：
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