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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

基本信息

批准号：
9976598
负责人：
ZIXU MAO
金额：
$ 47.2万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976598
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Animals Autopsy Biogenesis Brain 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 Link MAP Kinase 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 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 conditional knockout human disease hyperphosphorylated tau insight neurotoxicity novel p38 Mitogen Activated Protein Kinase progressive neurodegeneration protein complex stress kinase tau Proteins therapeutic target

项目摘要

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.

神经元对环境的变化高度敏感，并形成了动态适应感知和复制这些变化所造成的压力的过程。我们研究的长期目标是了解神经元对压力做出反应的机制。MiRNAs(MicroRNAs)是最近出现的一种发现了一类非编码的小RNA，参与调节许多细胞过程，包括压力。MiRNAs功能障碍参与了多种病理过程。MiRNA生物发生是由多个蛋白质复合体支配的几个紧密耦合的顺序步骤控制，并受错综复杂的监管。整个过程是在细胞核中通过长的初级miRNA的转换而启动的通过RNaseIII酶DROSHA转录成发夹结构的前体miRNA(前miRNAs)。是否 DROSHA本身是一个直接的监管目标尚不清楚。越来越多的数据表明，压力条件而miRNAs在几个层面上高度交织在一起。然而，直接调制的信号和通路 DROSHA在生理或病理应激条件下的情况仍有待确定。有多个一系列证据表明miRNAs对大脑功能和调节通路特别重要以及与遗传和散发性AD发病相关的关键基因。其中许多miRNAs本身就是在公元后发生了变化。此外，通过有条件地敲除神经元中的Dester来抑制miRNA的生物生成，这是在DROSHA下游阻断miRNA的生物生成，导致小鼠发展为进行性神经退行性变和类AD tau过度磷酸化。这可能提供了最有力的证据证明 MiRNA生物发生与阿尔茨海默病之间的潜在联系。然而，这些发现如何转化为动物AD 模型和人类疾病仍有待测试。最近，我们披露了各种压力条件对DROSHA施加了直接和严格的控制。这涉及到应激诱导的p38 MAPK依赖 DROSHA的磷酸化和抑制，以及DROSHA的丢失在应激状态下触发细胞死亡(分子细胞按下)。在一系列初步研究中，我们已经将这组关键发现扩展到初级皮质神经元结果表明：a)应激信号导致p38MAPK介导的直接磷酸化和DROSHA的抑制 B)β似乎参与了这一通路，并降低了初级皮质神经元中DROSHA的水平；c) 增加DROSHA保护神经元免受β诱导的毒性；以及d)核DROSHA的水平如下转基因阿尔茨海默病大鼠的大脑皮质和死后阿尔茨海默病大鼠的大脑中的蛋白质显著减少。加在一起，这些非常有意义的发现支持了一个有趣的假设，即β通过p38MAPK-DROSHA途径传递信号到抑制miRNA的生物生成，干扰神经元的动态平衡和存活。DROSHA的损失可能是参与阿尔茨海默病的神经退变过程。我们建议使用分子和细胞的组合方法用体外培养的方法评估DROSHA的缺失是否是β诱导的毒性和发病机制的基础初级神经元，一种新建立的阿尔茨海默病大鼠模型，以及人类死后阿尔茨海默病的大脑。