Toxicology Program, University of Michigan, Ann Arbor, MI 48109-2029, USA.
Chem Biol Interact. 2013 Mar 25;203(1):238-44. doi: 10.1016/j.cbi.2012.10.024. Epub 2012 Dec 3.
Neuropathy target esterase (NTE) was discovered by M.K. Johnson in his quest for the entity responsible for the striking and mysterious paralysis brought about by certain organophosphorus (OP) esters. His pioneering work on OP neuropathy led to the view that the biochemical lesion consisted of NTE that had undergone OP inhibition and aging. Indeed, nonaging NTE inhibitors failed to produce disease but protected against neuropathy from subsequently administered aging inhibitors. Thus, inhibition of NTE activity was not the culprit; rather, formation of an abnormal protein was the agent of the disorder. More recently, however, Paul Glynn and colleagues showed that whereas conventional knockout of the NTE gene was embryonic lethal, conditional knockout of central nervous system NTE produced neurodegeneration, suggesting to these authors that the absence of NTE rather than its presence in some altered form caused disease. We now know that NTE is the 6th member of a 9-protein family called patatin-like phospholipase domain-containing proteins, PNPLA1-9. Mutations in the catalytic domain of NTE (PNPLA6) are associated with a slowly developing disease akin to OP neuropathy and hereditary spastic paraplegia called NTE-related motor neuron disorder (NTE-MND). Furthermore, the NTE protein from affected individuals has altered enzymological characteristics. Moreover, closely related PNPLA7 is regulated by insulin and glucose. These seemingly disparate findings are not necessarily mutually exclusive, but we need to reconcile recent genetic findings with the historical body of toxicological data indicating that inhibition and aging of NTE are both necessary in order to produce neuropathy from exposure to certain OP compounds. Solving this mystery will be satisfying in itself, but it is also an enterprise likely to pay dividends by enhancing our understanding of the physiological and pathogenic roles of the PNPLA family of proteins in neurological health and disease, including a potential role for NTE in diabetic neuropathy.
神经毒性靶酯酶（NTE）是由 M.K. 约翰逊在寻找导致某些有机磷（OP）酯类引起的惊人且神秘瘫痪的原因时发现的。他在 OP 神经病学方面的开创性工作导致了这样一种观点，即生化损伤由经历了 OP 抑制和老化的 NTE 组成。事实上，非老化的 NTE 抑制剂未能产生疾病，但可防止随后给予的老化抑制剂引起的神经病。因此，抑制 NTE 活性不是罪魁祸首；相反，形成异常蛋白质才是疾病的原因。然而，最近保罗·格林和同事们表明，尽管常规敲除 NTE 基因是胚胎致死的，但中枢神经系统 NTE 的条件性敲除会导致神经退行性变，这表明这些作者认为缺乏 NTE 而不是其以某种改变形式存在会导致疾病。我们现在知道，NTE 是一个称为脂肪酶样磷脂酶结构域蛋白家族的 9 种蛋白中的第 6 种，PNPLA1-9。NTE（PNPLA6）催化结构域的突变与一种类似于 OP 神经病和遗传性痉挛性截瘫的缓慢发展疾病有关，称为 NTE 相关运动神经元疾病（NTE-MND）。此外，来自受影响个体的 NTE 蛋白具有改变的酶学特征。此外，密切相关的 PNPLA7 受胰岛素和葡萄糖调节。这些看似不同的发现不一定相互排斥，但我们需要将最近的遗传发现与历史上的毒理学数据结合起来，这些数据表明，要使某些 OP 化合物暴露引起神经病，必须抑制和老化 NTE。解决这个谜团本身就令人满意，但这也是一项有希望的事业，因为它可以增强我们对 PNPLA 蛋白家族在神经健康和疾病中的生理和病理作用的理解，包括 NTE 在糖尿病神经病中的潜在作用。
