Motor neuron disease due to neuropathy target esterase mutation: enzyme analysis of fibroblasts from human subjects yields insights into pathogenesis.
Motor neuron disease due to neuropathy target esterase mutation: enzyme analysis of fibroblasts from human subjects yields insights into pathogenesis.
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由于神经病靶酯酶突变引起的运动神经元疾病：人类受试者的成纤维细胞的酶分析可洞悉发病机理。
DOI：
10.1016/j.toxlet.2010.06.020
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发表时间：
2010-11-10
影响因子：
3.5
通讯作者：
Fink, John K.
中科院分区：
文献类型：
--
作者：
Hein, Nichole D.;Rainier, Shirley R.;Richardson, Rudy J.;Fink, John K.
关键词：
最近，我们发现神经病变靶酯酶（NTE）突变是常染色体隐性运动神经元病（NTE- mnd）的病因。随后，我们发现NTE- mnd突变降低了NTE催化结构域结构体的特异性活性（SA）并改变了抑制动力学。最近的初步结果表明，NTE在培养的人类皮肤成纤维细胞中表达，其他人已经使用成纤维细胞中表达的神经元蛋白突变形式作为神经遗传疾病的生物标志物。因此，本研究旨在验证NTE- mnd受试者培养的皮肤成纤维细胞中的NTE也表现出酶学特性的改变，这一假设通过米帕福（MIP）和毒死蜱（CPO）的SA和IC50值来评估。在纯合子M1012V成纤维细胞中，NTE SA减少到对照的65%（来自商业获得的成纤维细胞的野生型NTE），而在复合杂合子R890H/c2946_2947InsCAGC成纤维细胞中，NTE SA减少到对照的59-61%。MIP IC50值不受NTE突变的影响，但纯合子M1012V成纤维细胞的CPO IC50增加了4.5倍。有趣的是，在NTE插入c2946_2947InsCAGC杂合的无症状受试者的成纤维细胞中，观察到NTE SAs显著减少（40-43%）。这种插入预计会产生截断的NTE，缺少其催化结构域的最后235个残基。这些观察结果证实了NTE- mnd突变在体外降低了NTE SA。此外，在培养成纤维细胞中观察到的结果可以推广到神经系统事件，在NTE插入突变杂合子中，成纤维细胞NTE SA减少与NTE-MND发生之间缺乏相关性，这表明仅减少NTE SA不足以引起MND。
Recently, we identified neuropathy target esterase (NTE) mutation as the cause of an autosomal recessive motor neuron disease (NTE-MND). Subsequently, we showed that NTE-MND mutations reduced specific activity (SA) and altered inhibitory kinetics of NTE catalytic domain constructs. Recent preliminary results showed that NTE is expressed in cultured human skin fibroblasts, and others have used mutant forms of neuronal proteins expressed in fibroblasts as biomarkers of neurogenetic diseases. Therefore, the present study was carried out to test the hypothesis that NTE in cultured skin fibroblasts from NTE-MND subjects also exhibit altered enzymological properties assessed by SA and IC50 values of mipafox (MIP) and chlorpyrifos oxon (CPO). NTE SA was reduced to 65% of control (wild type NTE from commercially obtained fibroblasts) in homozygous M1012V fibroblasts and 59-61% of control in compound heterozygous R890H/c2946_2947InsCAGC fibroblasts. MIP IC50 values were unaffected by the NTE mutations, but the CPO IC50 increased 4.5-fold in homozygous M1012V fibroblasts. Interestingly, markedly reduced NTE SAs (40-43% of control) were observed in fibroblasts from asymptomatic subjects heterozygous for NTE insertion c2946_2947InsCAGC. This insertion is predicted to produce truncated NTE missing the last 235 residues of its catalytic domain. These observations confirm that NTE-MND mutations reduce NTE SA in vitro. Moreover, to the extent observations made in cultured fibroblasts may be generalized to events in the nervous system, lack of correlation between reduced fibroblast NTE SA and the occurrence of NTE-MND in NTE insertion mutation heterozygotes indicates that reduction of NTE SA alone is insufficient to cause MND.
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影响因子：
6.1
作者：
JOHNSON, MK
通讯作者：
JOHNSON, MK
影响因子：
4.1
作者：
JOHNSON, MK
通讯作者：
JOHNSON, MK
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3.7
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