The Role of Drosha in the Pathogenesis of Alzheimer's Disease

Drosha 在阿尔茨海默病发病机制中的作用

• 批准号: 9323608
• 负责人: ZIXU MAO
• 金额: $ 45.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323608
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Autopsy; Biogenesis; Brain; Brain Diseases; Calpain; Cell Death; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Cessation of life; Chronic; Cleaved cell; Complex; Coupled; Data; Degenerative Disorder; DiGeorge Syndrome; Disease; Distributional Activity; Environment; Enzymes; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Health; Homeostasis; Human; Individual; Knock-out; Link; MAP Kinase Gene; MAPK14 gene; Mediating; Methods; MicroRNAs; Microprocessor; Molecular; Mus; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Export; Nucleotides; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Peptide Hydrolases; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Physiological; Play; Population; Process; Proteins; Rattus; Regulation; Research; Research Personnel; Ribonuclease III; Role; Senile Plaques; Series; Signal Pathway; Signal Transduction; Small RNA; Stress; Structure; Testing; Toxic effect; Transcript; Transgenic Organisms; Translating; Treatment Efficacy; Untranslated RNA; abeta oligomer; abeta toxicity; biological adaptation to stress; brain cell; human disease; hyperphosphorylated tau; insight; neurotoxicity; novel; progressive neurodegeneration; protein complex; tau Proteins; therapeutic target

Neurons are highly sensitive to changes in their environment, and have developed dynamic adaptive processes to sense and copy with stress caused by such changes. The long-term goal of our research is to understand the mechanisms by which neurons respond to stress. MiRNAs (microRNAs) are a recently discovered class of non-coding small RNAs that are involved in regulating many cellular processes including stress. Dysfunction of miRNAs has been implicated in many pathological processes. MiRNA biogenesis is controlled by several tightly coupled sequential steps governed by multiple protein complexes and subjected to intricate regulation. The entire process is initiated in the nucleus by the conversion of the long primary miRNA transcripts to the hairpin structured precursor miRNA (pre-miRNAs) by the RNase III enzyme Drosha. Whether Drosha itself is a direct regulatory target is unknown. A growing body of data suggests that stress conditions and miRNAs are highly intertwined at several levels. However, signals and pathways directly modulating Drosha under either physiological or pathological stress condition remain to be identified. There are multiple lines of evidence indicating that miRNAs are especially important to the brain function and modulate pathways and key genes relevant to genetic and sporadic AD pathogenesis. Many of these miRNAS are themselves altered in AD. Furthermore, inhibiting miRNA biogenesis by conditionally knocking out Dicer in neurons, which blocks miRNA biogenesis at a step downstream of Drosha, causes mice to develop progressive neurodegeneration and AD-like tau hyperphosphorylation. This offers perhaps the strongest evidence for a potential link between miRNA biogenesis and AD. However, how these findings translate into animal AD models and human disease remains to be tested. Recently, we have revealed that a variety of stress conditions exert a direct and tight control of Drosha. This involves a stress-induced, p38 MAPK dependent phosphorylation and inhibition of Drosha, and loss of Drosha triggers cell death under stress (Molecular Cell in press). In a series of preliminary studies, we have extended this set of key findings to primary cortical neurons and shown that a) stress signals cause p38 MAPK-mediated direct phosphorylation and inhibition of Drosha in neurons; b) Aβ appears to engage this pathway and reduces the level of Drosha in primary cortical neurons; c) increasing Drosha protects neurons from Aβ-induced toxicity; and d) the levels of the nuclear Drosha are significantly reduced in the cortex of a transgenic AD rat and the postmortem AD brains. Together, these highly significant findings support an intriguing hypothesis that Aβ signals via p38 MAPK-Drosha pathway to inhibit miRNA biogenesis and interfere neuronal homeostasis and survival. Loss of Drosha may underlie in part the neurodegenerative process in AD. We propose to use a combination of molecular and cellular methods to assess whether loss of Drosha underlies Aβ-induced toxicity and pathogenesis using cultured primary neurons, a new established rat model of Alzheimer's disease, and human postmortem AD brains.

神经元对环境变化高度敏感，并发展了动态自适应 通过这种变化引起的压力，以感知和复制的过程。我们研究的长期目标是 了解神经元应对压力的机制。 mirnas（microRNA）是最近 发现的一类非编码的小RNA涉及调查许多蜂窝过程 压力。在许多病理过程中，miRNA功能障碍已被浸渍。 miRNA生物发生是 由几个紧密耦合的顺序步骤控制，由多个蛋白质复合物控制，并受到 复杂的调节。整个过程是通过长主要miRNA的转化在核中启动的 RNase III酶Drosha的发夹结构前体miRNA（前MIRNA）的转录本。无论 Drosha本身是一个直接的调节目标。越来越多的数据表明压力状况 miRNA在多个级别上高度交织在一起。但是，信号和路径直接调节 在身体或病理压力条件下的Drosha仍有待确定。有多个 表明miRNA对脑功能尤其重要并调节途径的证据线 以及与遗传和零星AD发病机理有关的关键基因。其中许多mirnas都是自己 广告变化。此外，通过在神经元中有条件敲出迪切剂来抑制miRNA生物发生， 在Drosha的逐步下游阻止miRNA生物发生，使小鼠发展为渐进式 神经变性和类似AD的TAU高磷酸化。这可能提供了有力的证据 miRNA生物发生与AD之间的潜在联系。但是，这些发现如何转化为动物广告 模型和人类疾病仍有待检验。最近，我们透露了各种压力 条件对Drosha产生直接而严格的控制。这涉及应力引起的p38 MAPK依赖性 Drosha的磷酸化和抑制作用，Drosha的丧失会触发胁迫下的细胞死亡（分子细胞中的分子细胞 按）。在一系列初步研究中，我们将这组关键发现扩展到原发性皮质神经元 并显示a）应力信号引起p38 MAPK介导的直接磷酸化和抑制Drosha在 神经元； b）Aβ似乎吸引了这一途径，并降低了原发性皮质神经元中的Drosha水平； c） 增加Drosha可保护神经元免受Aβ诱导的毒性。 d）核drosha的水平是 转基因AD大鼠的皮层和尸体后大脑的皮质显着降低。在一起，这些 高度显着的发现支持了一个有趣的假设，即Aβ通过p38 MAPK-DROSHA途径信号 抑制miRNA生物发生和干扰神经元稳态和生存。 Drosha的丧失可能是 部分AD中的神经退行性过程。我们建议使用分子和细胞的组合 评估Drosha丧失的方法是否是使用培养的Aβ诱导的毒性和发病机理的基础 原发性神经元，一种新的老阿尔茨海默氏病大鼠模型，人类术后大脑。