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

National Institute On Aging

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Abstract

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).