RNA-binding Factors Implicated in Neurogenesis, Alzheimer's Disease, and other Neurodegenerative Pathologies

与神经发生、阿尔茨海默病和其他神经退行性疾病相关的 RNA 结合因子

• 批准号: 10688820
• 负责人: Myriam Gorospe
• 金额: $ 40.21万
• 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/10688820
• 关键词: Abeta synthesis; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antisense Oligonucleotides; Area; Brain; Cells; Cellular biology; Collaborations; Collection; Developmental Biology; Drug Delivery Systems; Elderly; FMR1; FMRP; Gene Expression; Glioblastoma; Goals; Heterogeneous-Nuclear Ribonucleoprotein Group C; Heterogeneous-Nuclear Ribonucleoproteins; Human; Malignant Neoplasms; Medicine; Mitochondria; Mitochondrial RNA; Molecular Biology; Mus; Nature; Nerve Degeneration; Neurons; Parkinson Disease; Pathology; Peptides; Physiology; Plasma; Post-Transcriptional Regulation; Process; Production; Protein Biosynthesis; Proteolysis; RNA; RNA Binding; Regulation; Reporting; Role; Senile Plaques; Sirtuins; Testing; Time; Toxic effect; Work; age related; beta-site APP cleaving enzyme 1; circular RNA; extracellular vesicles; frontier; neurogenesis; programs; senescence; structural biology; transcriptomics

Several studies are underway in the RNA Regulation Section to investigate the gene expression programs that influence neuronal physiology and pathology, with particular emphasis on neurodegeneration. During this review period, we have studied the transcriptomic programs of senescent cells that modulate amyloid plaques in Alzheimers disease (AD). In this project area, we previously 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) (Lee et al., Nature Structural and Molecular Biology, 2010), as well as by the RBP HuD (Kang et al., Cell Reports 2014). This earlier led us to propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, Abeta. Work is underway to investigate the potential use of antisense oligonucleotides (ASOs) to lower HuD levels, which we hypothesize would in turn lower the levels of APP and BACE1 in human and mouse. After reporting the presence of mitochondrial RNA in Alzheimer's disease circulating extracellular vesicles (Kim et al., Frontiers in Cell and Developmental Biology, 2020), we have identified collections of circular RNAs differentially abundant in brains and plasma from AD patients (Cochran et al., Cells 2021). We also supported a number of collaborative studies that uncovered that loss of mitochondrial sirtuins (SIRT3) caises hyperexcitability of the neuronal network accelerates age-related A pathology, and sensitizes neurons to A toxicity (NeuroMolecular Medicine, 2021). In collaboration with the King lab, we reviewed the impact of an RBP that we have studied for a long time, HuR, on glioblastoma, a malignancy that increases with advancing age (Advanced Drug Delivery Reviews, 2022).

RNA调节部分正在进行几项研究，以调查影响神经元生理学和病理学的基因表达程序，特别强调神经变性。在这一审查期间，我们已经研究了衰老细胞的转录程序，调节淀粉样斑块在阿尔茨海默病（AD）。 在该项目领域中，我们先前报道了淀粉样前体蛋白（APP）的水平，其被切割以释放阿尔茨海默病标志肽Abeta，由RBP FMRP（脆性X智力低下蛋白）和hnRNP C（异质核核糖核蛋白C）调节（Lee et al.，Nature Structural and Molecular Biology，2010），以及RBP HuD（Kang et al. Cell Reports 2014）。这使我们提出HuD共同促进APP的产生及其淀粉样蛋白片段Abeta的切割。研究反义寡核苷酸（ASO）降低HuD水平的潜在用途的工作正在进行中，我们假设这反过来会降低人类和小鼠中APP和BACE1的水平。 在报道了阿尔茨海默病循环细胞外囊泡中线粒体RNA的存在之后（Kim等人，Frontiers in Cell and Developmental Biology，2020），我们已经鉴定了在来自AD患者的脑和血浆中差异丰富的环状RNA的集合（Cochran et al.细胞2021）。 我们还支持了一些合作研究，这些研究发现线粒体sirtuins（SIRT3）的缺失会导致神经元网络的过度兴奋性加速年龄相关的A病理学，并使神经元对A毒性敏感（NeuroMolecular Medicine，2021）。 与King实验室合作，我们回顾了我们长期研究的RBP HuR对胶质母细胞瘤的影响，胶质母细胞瘤是一种随着年龄增长而增加的恶性肿瘤（Advanced Drug Delivery Reviews，2022）。