Methylmercury toxicity in neural development

说明(申请人提供)：甲基汞(MeHg)是一种强烈的环境毒素，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新鲜和咸水鱼对人类构成重大风险。最近的证据表明，胎儿大脑是甲基汞中毒最敏感的靶器官。然而，针对发育中的神经系统的甲基汞毒性机制尚不清楚。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，探讨甲基汞毒性的机制。我们最近的研究通过阐明甲基汞的一种新的直接活性来诱导Notch受体及其配体Delta的蛋白分解来支持这一假说。Noch和Delta是高度保守的细胞表面信号蛋白，它们决定细胞的命运，并调节神经发育中的突起生长。这一新的机制涉及到甲基汞通过半胱氨酸开关机制诱导潜在的ADAM(一种去整合素和金属蛋白酶)细胞表面蛋白的激活。亚当斯通过促进Notch和Delta蛋白的切割来调节Notch信号。众所周知，亚当斯在其他几个细胞表面受体和配体上也有类似的作用，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；2)确定其他神经元特有的信号通路蛋白，这些蛋白可被甲基汞诱导的蛋白分解改变。我们将在果蝇模型系统中使用一种多学科的方法，包括在培养的神经元和活体中进行生化和基于细胞的分析。我们的分析将确定神经发育中的关键信号通路，这些通路是甲基汞诱导损伤的目标。这些信息将有助于指导预防甲基汞中毒的策略，例如通过对蛋白水解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.