Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA.
Department of Psychiatry, Indiana Alzheimer Disease Center, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Sci Rep. 2020 Jul 1;10(1):10781. doi: 10.1038/s41598-020-66394-y.
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 N-methyladeonsine (mA) on nuclear export of App mRNA. We utilized the mA dataset by Hsu and colleagues to identify mA 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 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 did not alter the nuclear/cytoplasmic abundance of App mRNA. Of 36 validated FMRP targets, 35 messages contained mA peaks but only Agap2 mRNA was selectively enriched in Fmr1 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) 与淀粉样 β 蛋白前体 (App) mRNA 结合并调节其翻译，但详细机制仍有待确定。App mRNA 的差异甲基化可能是 FMRP 结合、mRNA 定位和翻译效率的基础。我们试图确定 FMRP 和 N6-甲基腺苷 (mA) 在 App mRNA 核输出中的作用。我们利用 Hsu 及其同事的 mA 数据集来鉴定 App mRNA 中的 mA 位点，并确定 Fmr1 敲除小鼠大脑皮层中细胞质相对于细胞核中 mRNA 的丰度是否发生改变。鉴于 APP 加工为 Aβ 和可溶性 APP alpha (sAPPα) 有助于疾病表型，我们还研究了 Fmr1 是否与 APP 蛋白加工酶的核输出相关，包括β-位点淀粉样蛋白裂解酶 (Bace1)、解整合素和金属蛋白酶 (Adams) 和早老素 (Psen) 的核输出相关。Fmr1 并未改变 App mRNA 的核/质丰度。在 36 个经过验证的 FMRP 靶标中，有 35 个消息包含 mA 峰，但只有 Agap2 mRNA 选择性地富集在 Fmr1 核中。编码次要的α-分泌酶和γ-分泌酶的 APP 加工酶 Adam9 和 Psen1 mRNA 的丰度在野生型细胞质中选择性富集。
