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

Gp120 与神经元微管结合：突触简化的新机制

• 批准号: 9422907
• 负责人: Italo Mocchetti
• 金额: $ 23.33万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9422907
• 关键词: AIDS Dementia Complex; Binding; Brain; Brain Injuries; Brain Pathology; Bypass; CASP3 gene; CXCR4 Receptors; CXCR4 gene; Cell membrane; Cells; Cognitive deficits; Cytoskeleton; Data; Diagnosis; Eicosanoids; Endocytosis; Excitatory Amino Acids; Exhibits; Future; Goals; HIV; HIV Envelope Protein gp120; HIV Seropositivity; HIV-associated neurocognitive disorder; Homeostasis; Impairment; Individual; Inflammatory; Injectable; Interleukin-1; Knowledge; Mediating; Mediator of activation protein; Microtubules; Mitochondria; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurites; Neurologic; Neuronal Injury; Neurons; Organelles; Pathologic; Process; Proteins; Rattus; Receptor Signaling; Reporting; Silicon Dioxide; Synapses; TNF gene; Testing; Therapeutic; V3 Loop; Vascularization; Viral Proteins; alpha helix; beta Tubulin; chemokine; chemokine receptor; cytokine; design; effective therapy; env Gene Products; experimental study; factor A; injured; insight; nanoparticle; negative affect; neuron apoptosis; neuron loss; neuronal survival; neurotoxic; neurotoxicity; novel; overexpression; receptor; receptor binding; therapy development; tool; trafficking

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.

抽象的 突触核神经元损伤正在成为认知缺陷的重要介体 艾滋病毒阳性个体。然而，HIV的分子和细胞机制 轴突修剪的原因远非建立。这排除了对 神经系统并发症。最近的发现报告说，HIV固体包膜蛋白GP120 内吞成神经元并与微管蛋白β-3（TUBB3）结合，这是神经元的主要成分 微管（MT），这对于神经元功能至关重要。内吞GP120的神经元 表现出神经蛋白酶的缩回和caspase-3的激活，提出了内吞的假设 过程和与TUBB3的结合对于GP120介导的神经元损伤至关重要。在这个 探索性提案，我们将通过检查GP120-神经毒性在该假设中进行检验 存在将GP120从结合到TUBB3的化合物的存在（AIM 1）。 GP120 内部化是介导的CXCR4受体。区分趋化因子受体 信号传导和与MT的结合是神经毒性的机制，AIM 2中的实验将测试 中孔二氧化硅纳米颗粒在神经元内的递送是否具有神经毒性。 病毒蛋白如何与神经元细胞骨架相互作用的表征和负面 影响成熟的突触将为理解机制提供考虑的见解 基本的HIV相关神经认知障碍。如果成功，该提议将建立 GP120在其内部化后，通过与神经元MT结合并损害神经元。 这是GP120神经毒性的一种新型机制，如果证明，它将有助于设计 将抑制GP120神经毒性作用的化合物。