Gp120 binds to neuronal microtubules: a new mechanism for synaptic simplification

摘要 突触树突状神经元损伤正在成为认知功能障碍的重要中介 HIV阳性的个人。尽管如此，HIV如何通过分子和细胞机制 轴突修剪的原因仍远未确定。这排除了有效的治疗 神经系统并发症。最近的研究结果表明，艾滋病毒可溶的包膜蛋白gp120 被内吞到神经元中，并与神经元的主要成分微管蛋白β-3结合 微管(MT)是神经元功能所必需的。内吞gp120的神经元 表现出轴突回缩和caspase-3的激活，提出了内细胞 这一过程及其与TUBB3的结合在gp120介导的神经元损伤中起着至关重要的作用。在这 探索性建议，我们将通过检查gp120-神经毒性在 存在取代gp120与TUBB3结合的化合物(目标1)。Gp120 内化是CXCR4受体介导的。区分趋化因子受体 信号和与MTS的结合作为神经毒性的机制，在AIM 2中的实验将测试 介孔二氧化硅纳米颗粒在神经元内传递gp120是否具有神经毒性。 病毒蛋白如何与神经元细胞骨架相互作用和负向作用的特征 影响成熟突触将为理解这一机制提供相当大的见解 潜在的艾滋病毒相关神经认知障碍。如果成功，这项提议将建立 Gp120在内化后，通过与神经元MT结合并破坏神经元而损伤神经元。 这是一种新的gp120神经毒性机制，如果得到证实，将有助于设计 将抑制gp120的神经毒性作用的化合物。

Abstract Synaptodendritic neuronal injury is emerging as an important mediator of cognitive deficits in HIV-positive individuals. Nevertheless, the molecular and cellular mechanisms of how HIV causes axonal pruning are still far from established. This precludes effective treatment of the neurological complications. Recent findings report that the HIV soluble envelope protein gp120 is endocytosed into neurons and binds to tubulin β-3 (TUBB3), a major component of neuronal microtubules (MTs), which are essential for neuronal function. Neurons that endocytose gp120 exhibit neurite retraction and activation of caspase-3, raising the hypothesis that the endocytic process and the binding to TUBB3 are crucial for gp120-mediated neuronal injury. In this exploratory proposal, we will test this hypothesis by examining gp120-neurotoxicity in the presence of compounds that displace gp120 from binding to TUBB3 (AIM 1). Gp120 internalization is CXCR4 receptor mediated. To discriminate between chemokine receptor signaling and binding to MTs as a mechanism of neurotoxicity, experiments in AIM 2 will test whether the delivery of gp120 inside neurons by mesoporous silica nanoparticles is neurotoxic. The characterization of how viral proteins interact with the neuronal cytoskeleton and negatively affect mature synapses will provide considerable insights toward understanding the mechanism underlying HIV-associated neurocognitive disorders. If successful, this proposal will establish that gp120, after its internalization, injures neurons by binding to and damaging neuronal MTs. This is a novel mechanism of gp120 neurotoxicity that, if proven, will help in the design of compounds that will inhibit the neurotoxic effect of gp120.