FMRP Regulates the Nuclear Export of Adam9 and Psen1 mRNAs: Secondary Analysis of an N6-Methyladenosine Dataset

Abstract

Fragile X mental retardation protein (FMRP) binds to and regulates the translation of amyloid-β protein precursor (App) mRNA, but the detailed mechanism remains to be determined. Differential methylation of App mRNA could underlie FMRP binding, message localization and translation efficiency. We sought to determine the role of FMRP and N⁶-methyladeonsine (m⁶A) on nuclear export of App mRNA. We utilized the m⁶A dataset by Hsu and colleagues to identify m⁶A sites in App mRNA and to determine if the abundance of message in the cytoplasm relative to the nucleus is altered in Fmr1 knockout mouse brain cortex. Given that processing of APP to Aβ and soluble APP alpha (sAPPα) contributes to disease phenotypes, we also investigated whether Fmr1^KO associates with nuclear export of the mRNAs for APP protein processing enzymes, including β-site amyloid cleaving enzyme (Bace1), A disintegrin and metalloproteinases (Adams), and presenilins (Psen). Fmr1^KO did not alter the nuclear/cytoplasmic abundance of App mRNA. Of 36 validated FMRP targets, 35 messages contained m⁶A peaks but only Agap2 mRNA was selectively enriched in Fmr1^KO nucleus. The abundance of the APP processing enzymes Adam9 and Psen1 mRNA, which code for a minor alpha-secretase and gamma-secretase, respectively, were selectively enriched in wild type cytoplasm.