Prolongation of Chemically-Induced Methemoglobinemia in Mice Lacking α-synuclein: A Novel Pharmacologic and Toxicologic Phenotype.
Prolongation of Chemically-Induced Methemoglobinemia in Mice Lacking α-synuclein: A Novel Pharmacologic and Toxicologic Phenotype.
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缺乏α-突触核蛋白的小鼠中化学诱导的高铁血红蛋白血症的延长：一种新的药理学和毒理学表型。
DOI：
10.1016/j.toxrep.2015.02.013
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发表时间：
2015
影响因子：
--
通讯作者：
Nussbaum,RobertL
中科院分区：
文献类型：
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作者：
Kuo,Yien-Ming;Nussbaum,RobertL
α-突触核蛋白在帕金森病（PD）的遗传和组织病理学基础上被认为是发病机制的核心。它在胎儿中广泛表达，并在成人神经组织、红细胞和血小板中持续高度表达，而据报道，成人组织的其余部分很少或没有表达。尽管有细胞和分子证据表明α-突触核蛋白（Snca）在神经元功能（包括突触囊泡运输、神经递质释放、线粒体功能、脂质代谢、神经发生、神经保护和神经黑色素生物合成）中发挥作用，但消融编码α-突触核蛋白（Snca）基因的小鼠几乎没有或没有神经系统表型。因此，近20年的深入研究尚未最终揭示这种高度丰富的蛋白质在神经系统中的正常功能。有趣的是，α-突触核蛋白也显示出作为能够将Fe+3还原为Fe+2的铁还原酶的酶活性。鉴于α-突触核蛋白在红细胞中的丰富表达，我们着手探讨其在化学诱导的Fe+3高铁血红蛋白转化为正常Fe+2血红蛋白中的作用。对氨基苯丙酮及其活性代谢物4-羟基对氨基苯丙酮的体内实验表明，与Snca +/+小鼠相比，Snca −/−小鼠的高铁血红蛋白血症明显更严重，持续时间更长。然而，在红细胞的体外实验中，以及在包括神经系统在内的各种组织中α-突触核蛋白表达不同的基因工程小鼠品系的体内实验中，红细胞和肝脏的研究表明，与最初的假设相反，红细胞中α-突触核蛋白表达的缺乏与高铁血红蛋白血症的更高水平或更长的持续时间无关。相反，对化学诱导的高铁血红蛋白血症的更高敏感性与肝脏α-突触核蛋白表达的缺乏相关。我们在缺乏α-突触核蛋白的小鼠中发现了一种新的和强大的全动物表型，反映了其在异生物质解毒中迄今未被认识的作用。
The protein α-synuclein is considered central to the pathogenesis of Parkinson disease (PD) on genetic and histopathological grounds. It is widely expressed in fetal life and continues to be highly expressed in adult neural tissues, red blood cells and platelets, while the remainder of adult tissues are reported to have little or no expression. Despite cellular and molecular evidence for a role in neuronal function including synaptic vesicle trafficking, neurotransmitter release, mitochondrial function, lipid metabolism, neurogenesis, neuroprotection, and neuromelanin biosynthesis, mice ablated for the gene encoding α-synuclein (Snca) have little or no neurological phenotype. Thus, nearly 20 years of intensive study have yet to reveal conclusively what the normal function of this highly abundant protein is in the nervous system. Interestingly, α-synuclein has also been shown to have enzymatic activity as a ferrireductase capable of reducing Fe+3to Fe+2. Given its abundant expression in red blood cells, we set out to explore the role of α-synuclein in converting chemically-induced Fe+3methemoglobin to normal Fe+2hemoglobin. Initialin vivoexperiments with the potent methemoglobin inducer, para-aminopropiophenone and its active metabolite, 4-hydroxy para-aminopropiophenone, demonstrated significantly greater and more prolonged methemoglobinemia inSnca−/− mice compared toSnca+/+ mice.In vitroexperiments with red blood cells, however, andin vivoexperiments in genetically engineered mouse strains that differ in their α-synuclein expression in various tissues, including the nervous system, red blood cells and liver, revealed that contrary to the initial hypothesis, a lack of expression of α-synuclein in red blood cells did not correlate with higher levels or more prolonged duration of methemoglobinemia. Instead, the greater sensitivity to chemically induced methemoglobinemia correlated with the absence of hepatic α-synuclein expression. We have uncovered a new and robust whole-animal phenotype in mice lacking α-synuclein that reflects its hitherto unrecognized role in xenobiotic detoxification.