Glycogen synthase kinase-3beta: a setpoint for dopamine dysfunction in neuroAIDS

糖原合成酶激酶 3beta：神经艾滋病中多巴胺功能障碍的设定点

• 批准号: 7683974
• 负责人: SETH PERRY
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683974
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Accounting; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Age; Animal Model; Architecture; Attention; Binding; Bioenergetics; Biological Assay; Brain; Cell Death; Cell membrane; Cell model; Cells; Clinical Data; Corpus striatum structure; Coupled; Coupling; Data; Defect; Dementia; Disease; Dissection; Dopamine; DsRed; Enzymes; Exhibits; Exposure to; Fluorescence Resonance Energy Transfer; Functional disorder; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Hand; Highly Active Antiretroviral Therapy; Image; Immunologics; In Situ; In Vitro; Individual; Kinetics; Laboratories; Link; Maleimides; Measures; Mediating; Mediator of activation protein; Membrane; Metabolic; Methods; Microscopy; Mind; Modeling; Molecular; Molecular Biology; Mononuclear; Morbidity - disease rate; Mus; Nerve; Nerve Degeneration; Neuroglia; Neurologic; Neurologic Deficit; Neurons; Neuropsychology; Neurotoxins; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pattern; Phagocytes; Phosphotransferases; Physiological; Plant Roots; Platelet Activating Factor; Prevalence; Protein Isoforms; Proteins; Research; Role; Signal Transduction; Source; Speed; Structure; Substantia nigra structure; Surface; Synapses; Techniques; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Transfection; Translating; Viral Load result; Western Blotting; Wild Type Mouse; Work; aging population; alpha synuclein; animal data; base; brain tissue; dopamine system; dopamine toxicity; dopamine transporter; glycogen synthase kinase 3 beta; in vivo; in vivo Model; inhibitor/antagonist; macrophage; neuron apoptosis; neuron loss; neurotoxicity; prevent; public health relevance; response; success; synaptic function; synuclein; trafficking; uptake; valproate

DESCRIPTION (provided by applicant): HIV-associated neurologic disease (HAND) remains a source of significant morbidity, and is increasing in prevalence, despite success reducing viral load in HIV-infected individuals with highly active antiretroviral therapy (HAART). While HAART can frequently delay the onset or progression of HAND, and may in part reverse the course of HAND with timely initiation, it cannot always prevent HAND, and it cannot forever halt the course of HAND as HIV-infected individuals age, thus accounting for HAND's increased prevalence. Therefore exceptional need remains for adjunctive therapies that can directly address the neurologic deficits of the increasing and aging population of HIV-infected individuals. A large body of evidence suggests HAND pathogenesis results from a toxic milieu of secretory neurotoxins secreted from HIV-1 infected, brain-resident mononuclear phagocytes and glia, which act in concert to impart a range of toxic effects neuronal function, particularly synaptic function. Neuropathologic studies demonstrating neuronal apoptosis in brain tissue of patients that had neurologic deficits indicate that the degree of frank neuronal loss does not correlate well with pre-mortem neuropsychologic deficits. Rather, alterations in dendritic architecture and synaptic structure correlate far better with these deficits, and our laboratory and others have shown that the HIV neurotoxins Tat and platelet activating factor (PAF) adversely affect synaptic function, and may even render "normal" physiologic synaptic activity harmful in their presence. From this convergent evidence, we believe HAND arises from a reversible metabolic synaptic dysfunction, and is amenable to direct therapeutic intervention. The dopamine system appears particularly vulnerable in HAND, and there is evidence that a "reversible" synaptic dysfunction applies to dopaminergic synapses as well. Supported by others' complementary findings, we present a breadth of preliminary evidence here that dopamine transporter (DAT) activity and function is disrupted by the HIV neurotoxin Tat, resulting in hyperactive DAT activity and dopamine uptake at the synapse. We hypothesize this hyperactive DAT activity is: 1. Sufficient in itself to cause HAND deficits, and 2. May ultimately result in permanent nigral or striatal neuronal loss and neurologic deficit, consequent to unsustainable metabolic demands and/or enhanced auto-oxidative dopamine toxicity pre-synaptically, or over/under-stimulation of post-synaptic striatal connections. Mechanistically, binding of alpha-synuclein to DAT has been shown to increase membrane DAT in models of Parkinson's disease (PD). Separately, we have found significant roles for glycogen kinase three-beta (GSK-3beta) in models of HAND, and others' have implicated GSK-3beta in controlling alpha-synuclein activity. No direct links have yet been established between GSK and synuclein as mediators of DAT dysfunction in HAND (or PD), despite preliminary success of GSK- blockade as a potential therapeutic approach for HAND. The studies herein propose to explore these interactions as a possible root cause of dopaminergic dysfunction in neuroAIDS. PUBLIC HEALTH RELEVANCE This project proposes to study the mechanisms by which HIV-neurotoxins in the brain alter dopaminergic synapses, particularly activity of the dopamine transporter, to impart neurologic deficits in HIV Dementia, with the goal of developing adjunctive therapeutics for this disease.

描述（由申请人提供）：尽管成功降低了具有高度活跃的抗逆转录病毒疗法（HAART）的HIV感染者，但与HIV相关的神经疾病（HARD）仍然是发病率明显的来源，并且正在增加患病率。尽管Haart经常会延迟手的发作或进展，并且可能部分地及时地扭转了手的过程，但它不能总是阻止手，并且不能永远随着HIV感染的个体年龄的年龄而停止手的过程，从而考虑到手的患病率的增加。因此，辅助疗法仍然需要直接解决艾滋病毒感染者增加和老龄化的辅助疗法的特殊需求。大量证据表明，从HIV-1感染，脑居住的单核吞噬细胞和神经胶质中分泌的分泌神经毒素的有毒环境引起了手部发病机理，这些神经毒素和神经胶质的共同作用是赋予一系列毒性效应神经元功能，尤其是突触功能。神经病理学研究表明，神经系统缺陷的患者脑组织神经元细胞凋亡表明，坦率的神经元丧失程度与验尸前神经心理缺陷没有很好的相关性。相反，树突状结构和突触结构的改变与这些缺陷更好地相关，我们的实验室和其他人表明，HIV神经毒素TAT和血小板激活因子（PAF）对突触功能产生不利影响，甚至可能导致“正常”的生理突触活动在其存在下有害。从这种收敛的证据中，我们认为手是由可逆的代谢突触功能障碍产生的，并且可以直接进行治疗干预。多巴胺系统似乎特别容易受到伤害，并且有证据表明，“可逆”突触功能障碍也适用于多巴胺能突触。在其他人的补充发现的支持下，我们在这里提供了广泛的证据表明，多巴胺转运蛋白（DAT）活性和功能受到HIV神经毒素TAT的破坏，导致突触中的过度活动性DAT活性和多巴胺吸收。我们假设这种过度活跃的DAT活动是：1。足以引起手缺陷，2。最终可能导致永久性的或纹状体神经元或纹状体神经元损失和神经系统缺陷，这是由于无法固定的代谢需求和/或增强的自动氧化双胺毒性的毒性，或者较高的症状症状。从机械上讲，α-突触核蛋白与DAT的结合已被证明会增加帕金森氏病（PD）模型中的膜DAT。另外，我们发现糖原激酶三β（GSK-3BETA）在手模型中的重要作用，而其他人则与GSK-3BETA牵涉到控制α-突触核蛋白活性中的GSK-3Beta。尽管GSK-BLOCKADE是一种潜在的治疗方法，但GSK和Synuclein之间尚未建立直接连接作为Hand（或PD）的DAT功能障碍的介体。本文的研究建议探索这些相互作用，这是神经助剂多巴胺能功能障碍的可能根本原因。公共卫生相关性该项目建议研究大脑中的HIV-神经毒素改变多巴胺能突触，尤其是多巴胺转运蛋白的活性，以赋予HIV痴呆中神经系统缺陷，目的是为这种疾病开发辅助治疗剂。