Lulla Aaron, Barnhill Lisa, Bitan Gal, Ivanova Magdalena I, Nguyen Binh, O'Donnell Kelley, Stahl Mark C, Yamashiro Chase, Klärner Frank-Gerrit, Schrader Thomas, Sagasti Alvaro, Bronstein Jeff M
Department of Neurology, University of Los Angeles (UCLA), Los Angeles, California, USA.
Environ Health Perspect. 2016 Nov;124(11):1766-1775. doi: 10.1289/EHP141. Epub 2016 Jun 15.
Exposure to the commonly used dithiocarbamate (DTC) pesticides is associated with an increased risk of developing Parkinson disease (PD), although the mechanisms by which they exert their toxicity are not completely understood.
We studied the mechanisms of ziram's (a DTC fungicide) neurotoxicity in vivo.
Zebrafish (ZF) embryos were utilized to determine ziram's effects on behavior, neuronal toxicity, and the role of synuclein in its toxicity.
Nanomolar-range concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Because ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms, and ZF γ1 appears to be the closest functional homologue to α-syn. We found that recombinant ZF γ1 formed fibrils in vitro, and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity in a manner similar to that of α-syn. Importantly, knockdown of ZF γ1 with morpholinos and disruption of oligomers with the molecular tweezer CLR01 prevented ziram's DA toxicity.
These data show that ziram is selectively toxic to DA neurons in vivo, and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD. Citation: Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O'Donnell K, Stahl MC, Yamashiro C, Klärner FG, Schrader T, Sagasti A, Bronstein JM. 2016. Neurotoxicity of the Parkinson disease-associated pesticide ziram is synuclein-dependent in zebrafish embryos. Environ Health Perspect 124:1766-1775; http://dx.doi.org/10.1289/EHP141.
接触常用的二硫代氨基甲酸盐（DTC）类杀虫剂会增加患帕金森病（PD）的风险，尽管其产生毒性的机制尚未完全明确。
我们研究了福美锌（一种DTC类杀菌剂）在体内的神经毒性机制。
利用斑马鱼（ZF）胚胎来确定福美锌对行为、神经元毒性以及突触核蛋白在其毒性中的作用。
纳摩尔浓度范围的福美锌导致多巴胺能（DA）神经元选择性丧失，并损害游泳行为。由于福美锌会增加大鼠原代神经元培养物中α-突触核蛋白（α-syn）的浓度，我们研究了福美锌对ZFγ-突触核蛋白1（γ1）的影响。ZF表达3种突触核蛋白异构体，且ZFγ1似乎是与α-syn最接近的功能同源物。我们发现重组ZFγ1在体外形成纤维，并且在ZF胚胎中过表达ZFγ1会导致神经元聚集体的形成和神经毒性，其方式与α-syn相似。重要的是，用吗啉代寡核苷酸敲低ZFγ1以及用分子钳CLR01破坏寡聚体可预防福美锌的DA毒性。
这些数据表明福美锌在体内对DA神经元具有选择性毒性，且这种毒性是突触核蛋白依赖性的。这些发现对于理解杀虫剂可能导致PD的机制具有重要意义。引文：Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O'Donnell K, Stahl MC, Yamashiro C, Klärner FG, Schrader T, Sagasti A, Bronstein JM. 2016. 帕金森病相关杀虫剂福美锌的神经毒性在斑马鱼胚胎中是突触核蛋白依赖性的。环境健康展望124:1766 - 1775；http://dx.doi.org/10.1289/EHP141
