RNA-binding Factors Controlling Neurogenesis and Neurodegeneration

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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.