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). 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. In this review period, we reported the presence of mitochondrial RNA in Alzheimer's disease circulating extracellular vesicles (Kim et al., Frontiers in Cell and Developmental Biology, 2020) and identified collections of circular RNAs differentially abundant in brains and plasma from AD patients (Cochran et al., Cells 2021, in press). We also supported a number of collaborative studies that uncovered that SIRT3 haploinsufficiency accentuated the Alzheimers disease pathology by aggravating the loss of GABAergic interneurons and neuronal network hyperexcitability (Cheng et al., Journal of Neuroscience, 2019), and other studies that identified HuR as a factor that promotes Th17 cell differentiation and autoimmune neuroinflammation (Chen et al., Journal of Immunology, 2020). Finally, we reported that HuR was a central player in another collaborative study with the Woodhoo lab (Palomo-Irigoyen et al., Journal of Clinical Investigation, 2020), which uncovered that HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.