Methylmercury toxicity in neural development

描述（由申请人提供）：甲基汞（MeHg）是一种强效的环境毒素，会优先对神经系统造成损害。甲基汞在水生食物链中的生物积累通过饮食摄入淡水和咸水鱼类对人类构成重大风险。最近有证据表明，胎儿大脑是甲基汞中毒最易感的靶器官。然而，甲基汞对发育中的神经系统的毒性机制尚不清楚。我们将在甲基汞损害神经发育中受体信号通路功能的总体假设下研究甲基汞毒性的机制。我们最近的研究通过阐明甲基汞诱导Notch受体及其配体Delta蛋白水解的一种新的直接活性来支持这一假设。Notch和Delta是高度保守的细胞表面信号蛋白，在神经发育过程中决定细胞命运和调节神经突生长。这一新的机制涉及甲基汞通过半胱氨酸开关机制诱导潜在的亚当（一种崩解素和金属蛋白酶）细胞表面蛋白酶的激活。ADAMs通过促进Notch和Delta蛋白的切割来调节Notch信号。已知ADAMs以类似的方式作用于其他几种细胞表面受体和配体，这些受体和配体对神经发育至关重要。我们的两个主要目标是：1)确定甲基汞是如何改变发育中的神经系统中的Notch和Delta蛋白及其信号活性的；2)确定被甲基汞诱导的蛋白水解改变的其他神经元特异性信号通路蛋白。我们将在培养的神经元和果蝇模型系统中使用多学科方法，包括生化和基于细胞的检测。我们的分析将确定神经发育中的关键信号通路，这些信号通路是mehg诱导损伤的目标。这一信息将有助于制定预防甲基汞毒性的直接策略，例如通过蛋白酶抑制剂的药理管理。

DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a potent environmental toxin that preferentially causes damage to the nervous system. Bioaccumulation of MeHg in the aquatic food chain poses a significant risk to humans through dietary intake of fresh and saltwater fish. Recent evidence has established that the fetal brain is the most highly susceptible target organ in MeHg poisoning. However, mechanisms of MeHg toxicity that are specific to the developing nervous system are not well understood. We will investigate mechanisms of MeHg toxicity with the overall hypothesis that MeHg impairs function of receptor signaling pathways in neural development. Our recent studies support this hypothesis by elucidating a novel and direct activity of MeHg to induce proteolysis of the Notch receptor and its ligand, Delta. Notch and Delta are highly conserved cell surface signaling proteins that dictate cell fate decisions and regulate neurite outgrowth in neural development. This novel mechanism involves MeHg-induced activation of latent ADAM (a disintegrin and metalloprotease) cell surface proteases through a cysteine switch mechanism. ADAMs regulate Notch signals by promoting cleavages in the Notch and Delta proteins. ADAMs are known to act in a similar fashion on several other cell surface receptors and ligands that are central to neural development. Our two main objective are: 1) to determine how MeHg alters the Notch and Delta proteins and their signaling activity in the developing nervous system, and 2) to identify additional neuron-specific signaling pathway proteins that are altered by MeHg-induced proteolysis. We will use a multidisciplinary approach consisting of biochemical and cell-based assays in both cultured neurons and in vivo in a Drosophila model system. Our analyses will identify the critical signaling pathways in neural development that are targets for MeHg-induced damage. This information will help direct strategies for prevention of MeHg toxicity, for example through pharmacologic administration of protease inhibitors.