TY - JOUR
T1 - HuD regulates coding and noncoding RNA to induce APP→Aβ processing
AU - Kang, Min Ju
AU - Abdelmohsen, Kotb
AU - Hutchison, Emmette R.
AU - Mitchell, Sarah J.
AU - Grammatikakis, Ioannis
AU - Guo, Rong
AU - Noh, Ji Heon
AU - Martindale, Jennifer L.
AU - Yang, Xiaoling
AU - Lee, Eun Kyung
AU - Faghihi, Mohammad A.
AU - Wahlestedt, Claes
AU - Troncoso, Juan C.
AU - Pletnikova, Olga
AU - Perrone-Bizzozero, Nora
AU - Resnick, Susan M.
AU - deCabo, Rafael
AU - Mattson, Mark P.
AU - Gorospe, Myriam
N1 - Funding Information:
We thank H. Cai for providing reagents and information, J.H. Yoon for advice, and D. Phillips-Boyer, D. Nines, and J. Lucas for exceptional animal care. We appreciate the support of The Johns Hopkins University Alzheimer’s Disease Research Center. This work was funded by the NIA-IRP, NIH, by NIA P50AG05146 to J.C.T., and by NIDA R01DA034097 to N.P.-B.
PY - 2014/6/12
Y1 - 2014/6/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2014.04.050
DO - 10.1016/j.celrep.2014.04.050
M3 - Article
C2 - 24857657
AN - SCOPUS:84902318203
SN - 2211-1247
VL - 7
SP - 1401
EP - 1409
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -