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

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基因表达程序，特别是神经退行性变。在此回顾期间，我们研究了阿尔茨海默病(AD)中调节淀粉样蛋白斑块的衰老细胞的转录程序。 在这个项目领域，我们先前报道了淀粉样前体蛋白(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)(Lee等人，自然和分子生物学，2010年)以及RBP HUD(Kang等人，2014年细胞报告)的调节(APP被切割以释放阿尔茨海默病标志肽Abeta)。这使得我们早些时候提出，HUD共同促进APP的产生及其淀粉样变性片段Abeta的切割。目前正在研究使用反义寡核苷酸(ASO)来降低HUD水平的可能性，我们假设这将反过来降低人类和小鼠的APP和BACE1水平。 在报道了阿尔茨海默病患者循环细胞外小泡中存在线粒体RNA后(Kim等人，《细胞和发育生物学前沿》，2020)，我们已经确定了AD患者脑和血浆中丰富的环状RNA集合(Cochran等人，细胞2021)。 我们还支持了一些合作研究，发现线粒体sirtuins(SIRT3)的丢失会导致神经网络的过度兴奋，加速与年龄相关的A病理，并使神经元对A毒性敏感(神经分子医学，2021)。在与King实验室的合作下，我们回顾了我们研究了很长时间的RBP对胶质母细胞瘤的影响，胶质母细胞瘤是一种随着年龄的增长而增加的恶性肿瘤(高级药物传递评论，2022)。

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).