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）：尽管高效抗逆转录病毒治疗（HAART）成功降低了HIV感染者的病毒载量，但HIV相关神经系统疾病（HAND）仍然是显著发病率的来源，并且患病率正在增加。虽然HAART可以经常延迟HAND的发作或进展，并且可以通过及时启动部分逆转HAND的过程，但它不能总是预防HAND，并且随着HIV感染者的年龄增长，它不能永远停止HAND的过程，因此解释了HAND的患病率增加。因此，仍然特别需要能够直接解决HIV感染个体的增加和老龄化群体的神经功能缺陷的预防性治疗。大量的证据表明，HAND的发病机制是由HIV-1感染的脑内单核吞噬细胞和神经胶质细胞分泌的分泌性神经毒素的毒性环境引起的，这些神经毒素共同作用，赋予神经元功能，特别是突触功能一系列毒性作用。神经病理学研究表明，神经功能缺损患者的脑组织中存在神经元凋亡，这表明神经元缺损的程度与死亡前神经心理学缺损没有很好的相关性。相反，树突结构和突触结构的改变与这些缺陷的相关性要好得多，我们的实验室和其他实验室已经表明，HIV神经毒素达特和血小板活化因子（PAF）对突触功能有不利影响，甚至可能使“正常”的生理突触活动在它们的存在下有害。从这些证据来看，我们认为HAND是由可逆的代谢性突触功能障碍引起的，并且可以直接进行治疗干预。多巴胺系统在HAND中显得特别脆弱，并且有证据表明“可逆的”突触功能障碍也适用于多巴胺能突触。在其他人的补充研究结果的支持下，我们提出了一个初步的证据表明，多巴胺转运蛋白（DAT）的活性和功能被HIV神经毒素达特破坏，导致过度活跃的DAT活性和突触处的多巴胺摄取。我们假设这种过度活跃的DAT活动是：1。本身足以导致手缺陷，2。可能最终导致永久性黑质或纹状体神经元损失和神经功能缺损，导致不可持续的代谢需求和/或突触前增强的自氧化多巴胺毒性，或突触后纹状体连接的过度/刺激不足。在机理上，已经显示α-突触核蛋白与DAT的结合增加帕金森病（PD）模型中的膜DAT。另外，我们已经发现糖原激酶3-β（GSK-3 β）在HAND模型中的重要作用，其他人也暗示GSK-3 β控制α-突触核蛋白活性。GSK和突触核蛋白作为HAND（或PD）中DAT功能障碍的介导物之间尚未建立直接联系，尽管GSK-阻断作为HAND的潜在治疗方法已取得初步成功。本文的研究建议探索这些相互作用作为神经艾滋病多巴胺能功能障碍的可能根本原因。公共卫生相关性本项目旨在研究大脑中的HIV神经毒素改变多巴胺能突触的机制，特别是多巴胺转运蛋白的活性，从而导致HIV痴呆症的神经功能缺陷，目的是开发这种疾病的预防性治疗方法。