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.

脆性 X 智力低下蛋白 (FMRP) 结合并调节淀粉样蛋白 β 蛋白前体 ( App ) mRNA 的翻译，但详细机制仍有待确定。App mRNA 的差异甲基化可能是 FMRP 结合、信息定位和翻译效率的基础。我们试图确定 FMRP 和 N ⁶ -甲基腺苷酸 (m ⁶ A) 对App mRNA核输出的作用。我们利用Hsu 及其同事的 m ⁶ A 数据集来识别App mRNA 中的m ⁶ A 位点，并确定Fmr1 中细胞质中相对于细胞核的信息丰度是否发生了改变敲除小鼠大脑皮层。鉴于 APP 加工成 Aβ 和可溶性 APP α (sAPPα) 有助于疾病表型，我们还研究了Fmr1 ^KO是否与 APP 蛋白加工酶的 mRNA 核输出相关，包括 β 位点淀粉样蛋白切割酶 (Bace1)、A去整合素和金属蛋白酶 (Adams) 和早老素 (Psen)。Fmr1 ^KO不改变App mRNA的核/细胞质丰度。在 36 个经过验证的 FMRP 目标中，35 个消息包含 m ⁶ A 峰，但只有Agap2 mRNA 在Fmr1 ^KO核中选择性富集。APP 加工酶Adam9和Psen1 mRNA 分别编码次要 α-分泌酶和 γ-分泌酶，在野生型细胞质中选择性富集。