Plate Jennifer, Sassen Wiebke A, Hassan Ahmed H, Lehne Franziska, Köster Reinhard W, Kruse Tobias
Institute of Plant Biology, TU Braunschweig, Braunschweig, Germany.
Zoology Institute, Cellular and Molecular Neurobiology, TU Braunschweig, Braunschweig, Germany.
Front Pharmacol. 2019 Apr 2;10:122. doi: 10.3389/fphar.2019.00122. eCollection 2019.
Sulfite is a neurotoxin, which is detoxified by the molybdenum cofactor (Moco)-dependent enzyme sulfite oxidase (SOX). In humans, SOX deficiency causes the formation of the glutamate analog S-Sulfocysteine (SSC) resulting in a constant overstimulation of ionotropic glutamatergic receptors. Overstimulation leads to seizures, severe brain damage, and early childhood death. SOX deficiency may be caused either by a mutated gene or by mutations in one of the genes of the multi-step Moco biosynthesis pathway. While patients affected in the first step of Moco biosynthesis can be treated by a substitution therapy, no therapy is available for patients affected either in the second or third step of Moco biosynthesis or with isolated SOX deficiency. In the present study, we used a combination of behavior analysis and vital dye staining to show that SSC induces increased swimming, seizure-like movements, and increased cell death in the central nervous system of zebrafish larvae. Seizure-like movements were fully revertible upon removal of SSC or could be alleviated by a glutamatergic receptor antagonist. We conclude that in zebrafish SSC can chemically induce phenotypic characteristics comparable to the disease condition of human patients lacking SOX activity.
亚硫酸盐是一种神经毒素，可被钼辅因子（Moco）依赖性酶亚硫酸盐氧化酶（SOX）解毒。在人类中，SOX缺乏会导致谷氨酸类似物S-磺基半胱氨酸（SSC）的形成，从而导致离子型谷氨酸能受体持续过度刺激。过度刺激会导致癫痫发作、严重脑损伤和儿童早期死亡。SOX缺乏可能是由基因突变或多步骤Moco生物合成途径中一个基因的突变引起的。虽然在Moco生物合成第一步受到影响的患者可以通过替代疗法进行治疗，但对于在Moco生物合成第二步或第三步受到影响或患有孤立性SOX缺乏的患者则没有可用的治疗方法。在本研究中，我们结合行为分析和活体染料染色表明，SSC会导致斑马鱼幼体中枢神经系统中游泳增加、癫痫样运动增加以及细胞死亡增加。去除SSC后，癫痫样运动可完全恢复，或者可通过谷氨酸能受体拮抗剂缓解。我们得出结论，在斑马鱼中，SSC可以化学诱导出与缺乏SOX活性的人类患者疾病状况相当的表型特征。
