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: 7554519
• 负责人: SETH PERRY
• 金额: $ 19.25万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554519
• 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; Chromosome Pairing; Clinical Data; Corpus striatum structure; Coupled; Coupling; Data; Defect; Dementia; Depth; 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; Public Health; Range; 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; 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）：hiv相关神经系统疾病（HAND）仍然是一个重要的发病率来源，并且患病率正在增加，尽管在hiv感染者中使用高效抗逆转录病毒治疗（HAART）成功地降低了病毒载量。虽然HAART经常可以延缓HAND的发病或进展，并可能在一定程度上及时开始逆转HAND的病程，但它不能总是预防HAND，也不能随着艾滋病毒感染者年龄的增长而永远停止HAND的病程，因此解释了HAND的患病率增加。因此，对辅助疗法的特殊需求仍然存在，这些辅助疗法可以直接解决艾滋病毒感染者日益增加和老龄化人口的神经功能缺陷。大量证据表明，HAND的发病机制是由HIV-1感染、脑内单核吞噬细胞和胶质细胞分泌的分泌性神经毒素的毒性环境引起的，它们共同作用，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，这表明直率的神经元丢失程度与死前神经心理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有更好的相关性，我们的实验室和其他实验室已经表明，HIV神经毒素Tat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变得有害。从这些趋同的证据来看，我们认为HAND是由可逆的代谢性突触功能障碍引起的，可以直接进行治疗干预。多巴胺系统在HAND中显得特别脆弱，有证据表明，多巴胺能突触也存在“可逆”的突触功能障碍。在其他人的补充发现的支持下，我们在这里提出了广泛的初步证据，证明多巴胺转运蛋白（DAT）的活性和功能被HIV神经毒素Tat破坏，导致DAT活性过度活跃和突触多巴胺摄取。我们假设这种过度活跃的DAT活动是：1。这本身就足以导致HAND缺陷，2。由于不可持续的代谢需求和/或突触前或突触后纹状体连接的过度/不足刺激，可能最终导致永久性的神经或纹状体神经元损失和神经功能缺陷。从机制上讲，α -突触核蛋白与DAT的结合已被证明可以增加帕金森病（PD）模型中的膜DAT。另外，我们发现糖原激酶3 - β (gsk -3 β)在HAND模型中的重要作用，其他研究也表明gsk -3 β在控制α -突触核蛋白活性中起着重要作用。尽管GSK阻断作为一种潜在的HAND治疗方法取得了初步成功，但GSK和突触核蛋白作为HAND（或PD）中DAT功能障碍的介质之间尚未建立直接联系。本研究旨在探讨这些相互作用作为神经艾滋病患者多巴胺能功能障碍的可能根本原因。该项目旨在研究大脑中HIV-神经毒素改变多巴胺能突触，特别是多巴胺转运蛋白活性的机制，从而导致HIV痴呆患者的神经功能缺陷，目的是开发针对该疾病的辅助治疗方法。