title: HuD regulates coding and noncoding RNA to induce APP→Aβ processing.
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.
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Emmette R
authors.initials: ER
authors.lastname: Hutchison
authors.affiliation: Translational Gerontology Branch, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Grammatikakis
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Noh
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Faghihi
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Perrone-Bizzozero
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Resnick
authors.affiliation: Translational Gerontology Branch, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA. Electronic address: myriam-gorospe@nih.gov.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020871:RNA Stability; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D016229:Amyloid beta-Peptides; D051959:ELAV Proteins; D062085:RNA, Long Noncoding; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse