RNA-binding Factors Controlling Neurogenesis and Neurodegeneration

控制神经发生和神经变性的 RNA 结合因子

• 批准号: 8931550
• 负责人: Myriam Gorospe
• 金额: $ 61.77万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8931550
• 关键词: Abeta synthesis; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Brain; Cells; Cleaved cell; Code; Complement; Enzymes; Fragile X Mental Retardation Protein; Gene Expression; Gene Expression Regulation; Goals; Heterogeneous-Nuclear Ribonucleoprotein Group C; Heterogeneous-Nuclear Ribonucleoproteins; Individual; Link; Malignant Neoplasms; Messenger RNA; Mus; Nerve Degeneration; Nervous system structure; Neurons; Parkinson Disease; Pathogenesis; Pathology; Patients; Peptides; Physiology; Process; Production; Protein Biosynthesis; Proteolysis; RNA; RNA Binding; Regulation; Reporting; Role; Site; Superior temporal gyrus; Testing; Tissues; Topoisomerase; Translations; Untranslated RNA; Untranslated Regions; Work; beta-site APP cleaving enzyme 1; neurogenesis; novel; overexpression; protein function

Several studies are underway in the RNA Regulation Section to investigate the RBPs and ncRNAs that influence neuronal physiology and pathology, with particular emphasis on neurodegeneration. During this review period, we have studied the role of several RBPs and ncRNAs implicated in Alzheimers disease (AD) as well as other pathologies of the nervous system. We recently reported that the levels of amyloid precursor protein (APP), which is cleaved to release the Alzheimers disease hallmark peptide Abeta, was regulated by RBPs FMRP (fragile X mental retardation protein) and hnRNP C (heterogeneous nuclear ribonucleoprotein C). We further discovered that FMRP and hnRNPC associated with the coding region of APP mRNA in a competitive manner and repressed or enhanced APP translation, respectively. Expanding upon this work, we collaborated with Weidong Wangs group (LG, NIA), in studies that revealed that FMRP function was modulated by a novel RNA topoisomerase activity (Xu et al., Nat. Neurosci 2013). During this review period, we have also identified several targets of the RBP HuD that are linked to Alzheimer's disease (AD) pathogenesis. HuD interacted with the 3' UTRs of APP mRNA (encoding amyloid precursor protein) and BACE1 mRNA (encoding β-site APP-cleaving enzyme 1) and increased the half-lives of these mRNAs. HuD also associated with and stabilized the long noncoding (lnc)RNA BACE1AS, which partly complements BACE1 mRNA and enhances BACE1 expression. Consistent with HuD promoting production of APP and APP-cleaving enzyme, we found that the levels of APP, BACE1, BACE1AS, and Aβ were higher in the brain of HuD-overexpressing mice. Importantly, cortex (superior temporal gyrus) from patients with AD displayed significantly higher levels of HuD and, accordingly, elevated APP, BACE1, BACE1AS, and Aβ than did cortical tissue from healthy age-matched individuals. These findings, which appeared in Cell Reports (Kang et al., 2014) led us to propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, Aβ.

RNA调节科正在进行几项研究，以调查影响神经生理学和病理学的限制性商业惯例和核糖核酸酶，特别强调神经退行性变。在此综述期间，我们研究了与阿尔茨海默病(AD)以及其他神经系统病理有关的几种RBPs和ncRNAs的作用。 我们最近报道，淀粉样前体蛋白(APP)的水平受到RBPs FMRP(脆性X智力低下蛋白)和hnRNP C(异质核核糖核蛋白C)的调节，APP被切割后释放出阿尔茨海默病标志肽Abeta。我们进一步发现，FMRP和HNRNPC分别以竞争的方式与APP mRNA的编码区结合，并抑制或增强APP的翻译。在这项工作的基础上，我们与卫东Wangs小组(LG，NIA)合作，研究发现FMRP功能受一种新的RNA拓扑异构酶活性的调节(Xu等人，NAT)。Neurosci 2013)。 在此回顾期间，我们还确定了RBP HUD的几个与阿尔茨海默病(AD)发病机制有关的靶点。HUD与APP mRNA(编码淀粉样前体蛋白)和BACE1mRNA(编码APP裂解酶1)的3‘端UTRs相互作用，延长了这些mRNAs的半衰期。HUD还与长非编码(LNC)RNA BACE1AS相关并稳定，BACE1AS部分补充BACE1 mRNA，增强BACE1表达。与HUD促进APP和APP裂解酶的产生一致，我们发现HUD过度表达的小鼠大脑中APP、BACE1、BACE1AS和A&#946；的水平更高。重要的是，AD患者的大脑皮质(颞上回)显示出显著更高的HUD水平，相应地，APP、BACE1、BACE1AS和A&#946；比年龄匹配的健康人的皮质组织更高。这些发现发表在细胞报告(Kang等人，2014)上，这导致我们提出HUD共同促进APP的产生及其淀粉样变片段A&#946；的切割。