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.

摘要 突触-树突状神经元损伤正在成为认知缺陷的重要介质， 艾滋病毒阳性者。尽管如此，艾滋病病毒如何 轴突修剪的原因还远未建立。这就妨碍了有效治疗 神经系统并发症最近的研究结果表明，HIV可溶性包膜蛋白gp 120 被内吞到神经元中并结合微管蛋白β-3（TUBB 3），微管蛋白β-3是神经元的主要成分， 微管（MT），这是神经元功能所必需的。内吞gp 120的神经元 表现出神经突收缩和caspase-3的激活，提出了内吞作用的假设， 在gp 120介导的神经元损伤过程中，与TUBB 3的结合至关重要。在这 探索性的建议，我们将通过检查gp 120-神经毒性来测试这一假设， 存在取代gp 120与TUBB 3（AIM 1）结合的化合物。Gp120 内化是CXCR 4受体介导的。区分趋化因子受体 作为神经毒性机制的信号传导和与MT结合，AIM 2的实验将测试 介孔二氧化硅纳米颗粒在神经元内递送GP 120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并产生负面影响的表征 影响成熟的突触将提供相当多的见解， 潜在的HIV相关神经认知障碍如果成功的话，这一提议将建立 gp 120在其内化后通过结合并损伤神经元MT而损伤神经元。 这是一种新的gp 120神经毒性机制，如果得到证实，将有助于设计 将抑制GP 120的神经毒性作用的化合物。