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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.

神经元对其环境的变化高度敏感，并已发展出动态适应性感受和复制这些变化所带来的压力的过程。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。 miRNA (microRNA) 是最近发现了一类非编码小RNA，它们参与调节许多细胞过程，包括压力。 miRNA 的功能障碍与许多病理过程有关。 miRNA 的生物发生是由多个紧密耦合的连续步骤控制，由多个蛋白质复合物控制并受到复杂的监管。整个过程是通过长初级 miRNA 的转换在细胞核中启动的通过 RNase III 酶 Drosha 转录为发夹结构的前体 miRNA（pre-miRNA）。无论 Drosha本身是否是直接监管目标尚不清楚。越来越多的数据表明，压力条件并且 miRNA 在多个层面上高度交织在一起。然而，信号和通路直接调节 Drosha 在生理或病理应激条件下仍有待确定。有多个一系列证据表明 miRNA 对大脑功能和调节通路特别重要以及与遗传和散发性 AD 发病机制相关的关键基因。许多这些 miRNAS 本身就是公元时改变了。此外，通过有条件地敲除神经元中的 Dicer 来抑制 miRNA 生物合成，阻断 Drosha 下游步骤的 miRNA 生物发生，导致小鼠发育进行性神经退行性变和 AD 样 tau 蛋白过度磷酸化。这或许提供了最有力的证据 miRNA 生物发生与 AD 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，我们发现各种压力条件对 Drosha 产生直接而严格的控制。这涉及应激诱导的 p38 MAPK 依赖性 Drosha 的磷酸化和抑制，以及 Drosha 的缺失会在压力下触发细胞死亡（Molecular Cell in 按）。在一系列初步研究中，我们将这组关键发现扩展到初级皮质神经元并表明 a) 应激信号导致 p38 MAPK 介导的直接磷酸化和 Drosha 的抑制神经元； b) Aβ 似乎参与了该通路并降低了初级皮质神经元中 Drosha 的水平； c) 增加 Drosha 可保护神经元免受 Aβ 诱导的毒性； d) 核 Drosha 的水平为转基因 AD 大鼠的皮质和死后 AD 大脑的皮质显着减少。在一起，这些非常重要的发现支持一个有趣的假设，即 Aβ 通过 p38 MAPK-Drosha 通路发出信号抑制 miRNA 生物发生并干扰神经元稳态和存活。失去 Drosha 可能是 AD 中神经退行性过程的一部分。我们建议结合使用分子和细胞使用培养物评估 Drosha 缺失是否是 Aβ 诱导的毒性和发病机制的基础原代神经元、新建立的阿尔茨海默病大鼠模型和人类死后 AD 大脑。