HIV modulation of BAG3 impacting quality control of Tau in neuronal cells

HIV 对 BAG3 的调节影响神经元细胞中 Tau 的质量控制

基本信息

批准号：
9922215
负责人：
Kamel Khalili
金额：
$ 39.63万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922215
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Animal Model Animals Apoptosis Attention Autophagocytosis BAG3 gene Biochemical Bioenergetics Brain CRISPR/Cas technology Calcium Signaling Cause of Death Cell Culture Techniques Cell physiology Cells Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Data Deposition Development Disease Down-Regulation Energy Metabolism Ensure Environment Equilibrium Event Excision Generations Genome HIV HIV Infections HIV Seronegativity HIV Seropositivity HIV tat Protein HIV-1 HIV-associated neurocognitive disorder Heat-Shock Proteins 70 Homeostasis In Vitro Infection Interruption Investigation Laboratories Life Light Mediating Membrane Potentials Memory Microelectrodes Microtubule-Associated Proteins Microtubules Mitochondria Modeling Molecular Molecular Chaperones Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organelles Outcome Outcome Study Pathogenesis Pathogenicity Pathway interactions Patients Physiological Process Production Proteins Quality Control Risk Risk Factors Role Signal Transduction Stress Stress-Induced Protein System Thinking Toxic effect Transgenic Animals United States Up-Regulation Viral Proteins Virus aging brain antiretroviral therapy brain tissue endoplasmic reticulum stress experimental study human old age (65+)in vivo interest misfolded protein mitochondrial membrane mutant neuron loss neuronal circuitry neurotoxic parkin gene/protein premature protein aggregation proteostasis small hairpin RNA tat Protein tau Proteins tau aggregation tau phosphorylation tau-1 transmission process treatment effect

项目摘要

PROJECT SUMMARY It is estimated that more than 10% of the 1.1 million HIV positive patients in United States will be over 65 years old in less than ten years, a critical stage in life where the the risk for developing Alzheimer’s disease (AD) increases. Earlier results from clinical studies showed several abnormalities including difficulties with memory, thinking, and reasoning become more common in older HIV positive patients, implying that their risk factors may be elevated when compared with their HIV negative counterparts. This notion brings up the concept that HIV infection, even in patients whose virus is well controlled by antiretroviral therapy (ART), may be more prone to developing neurodegenerative disorders including AD. Considering the inability of ART to effectively suppress expression of viral proteins, including HIV Tat, which is a profoundly neurotoxic protein, we envision a scenario in which, by dysregulating the protein quality control (PQC) pathway, Tat may perturb homeostasis of key proteins associated with the pathogenesis of AD and set the stage for the development of disease. Several data from our and other laboratories support this concept. First, we demonstrated that Tat inhibits expression of BAG3, a co-chaperone/partner of HSP70 that is involved in the removal of dysfunctional and obsolete organelles including mitochondria through a process called mitophagy, and participates in autophagy and clearance of damaged and misfolded proteins by the protein quality control (PQC) pathway. Second, activation of BAG3 is concurrent with a decrease in the level of phosph-tau and an increase in the clearance of tau in neuronal cells. Third, soon after destabilization of microtubules, tau associates with Hsp70/Hsc70, a key partner of BAG3. Fourth, induction of Tat in the brains of transgenic animals increases accumulation of phospho-tau. Thus, Tat- mediated reduction in the level of BAG3 may have a damaging effect on neuronal cells by interrupting the process that ensures intracellular removal of the toxic from of tau, yet maintains the healthy species of tau that is critical for neuronal cell function. Hyper-phosphorylation of tau, which contributes to its misfolding and toxicity, may be attributed to Tat via induction of ROS, ER stress, and mitochondrial dysfunctionality. The latter is of particular interest as truncated tau has been implicated in dysregulation of mitochondrial dynamics and healty energy metabolism. These observations prompted us to hypothesize that, on one hand, Tat impacts the quality and concentration of proper levels of functional tau and the clearance of its toxic form by suppressing expression of BAG3, and on the other hand, Tat contributes to the generation of the toxic tau and dysfunctionality of bioenergetic pathways and mitochondria by inducing stress conditions in cells. To examine this model, we will employ in vitro primary neuronal cultures, ex vivo animal brain tissue, and an in vivo animal model to unravel the underlying molecular basis of HIV-1/Tat-induced perturbation of PQC and homeostasis of tau in neuronal cell function.

项目概要据估计，美国110万艾滋病毒阳性患者中超过10%年龄在65岁以上不到十年就老了，这是人生的关键阶段，有患阿尔茨海默病 (AD) 的风险早期的临床研究结果显示出一些异常现象，包括记忆困难、思考和推理在老年艾滋病毒阳性患者中变得更加普遍，这意味着他们的危险因素可能与 HIV 阴性人群相比，这一概念提出了 HIV 阴性的概念。感染，即使是在病毒通过抗逆转录病毒治疗（ART）得到很好控制的患者中，也可能更容易发生考虑到 ART 无法有效抑制包括 AD 在内的神经退行性疾病。病毒蛋白的表达，包括 HIV Tat，这是一种具有深度神经毒性的蛋白，我们设想了一个场景其中，通过失调蛋白质质量控制 (PQC) 途径，Tat 可能会扰乱关键的稳态与 AD 发病机制相关的蛋白质并为疾病的发展奠定了基础。我们和其他实验室支持这一概念，首先，我们证明 Tat 抑制 BAG3 的表达。 HSP70 的共伴侣/伙伴，参与去除功能失调和过时的细胞器通过称为线粒体自噬的过程包括线粒体，并参与自噬和清除其次，BAG3 的激活是通过蛋白质质量控制 (PQC) 途径来破坏和错误折叠的蛋白质。与此同时，神经元细胞中磷酸化 tau 蛋白水平降低，tau 蛋白清除率增加。第三，微管不稳定后不久，tau 蛋白就会与 BAG3 的关键伙伴 Hsp70/Hsc70 结合。第四，转基因动物大脑中Tat的诱导增加了磷酸tau蛋白的积累，因此，Tat-。 BAG3 水平介导的降低可能会通过中断神经元细胞的确保细胞内去除 tau 毒素的过程，同时保持 tau 蛋白的健康状态 tau 蛋白的过度磷酸化对神经细胞功能至关重要，这会导致其错误折叠和毒性，可能归因于 Tat 通过诱导 ROS、ER 应激和线粒体功能障碍。人们特别感兴趣，因为截短的 tau 蛋白与线粒体动态和健康失调有关这些观察结果促使我们认识到，一方面，Tat 会影响质量。功能性 tau 蛋白的适当水平浓度以及通过抑制表达清除其毒性形式 BAG3，另一方面，Tat 有助于有毒 tau 的产生和功能失调为了检查这个模型，我们将通过诱导细胞中的应激条件来研究生物能途径和线粒体。利用体外原代神经元培养物、离体动物脑组织和体内动物模型来揭示 HIV-1/Tat 诱导的神经元细胞中 PQC 扰动和 tau 稳态的潜在分子基础功能。