HuD regulates coding and noncoding RNA to induce APP→Aβ processing

Min Ju Kang, Kotb Abdelmohsen, Emmette R. Hutchison, Sarah J. Mitchell, Ioannis Grammatikakis, Rong Guo, Ji Heon Noh, Jennifer L. Martindale, Xiaoling Yang, Eun Kyung Lee, Mohammad A. Faghihi, Claes Wahlestedt, Juan C. Troncoso, Olga Pletnikova, Nora Perrone-Bizzozero, Susan M. Resnick, Rafael deCabo, Mark P. Mattson, Myriam Gorospe

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The primarily neuronal RNA-binding protein HuD is implicated in learning and memory. Here, we report the identification of several HuD target transcripts 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, 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. We propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, Aβ.

Original languageEnglish (US)
Pages (from-to)1401-1409
Number of pages9
JournalCell Reports
Volume7
Issue number5
DOIs
StatePublished - Jun 12 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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