Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Koch Institute for Integrative Cancer Research; Center for Precision Cancer Medicine; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Prog Neurobiol. 2022 Oct;217:102316. doi: 10.1016/j.pneurobio.2022.102316. Epub 2022 Jul 14.
The RNA binding protein ELAVL4/HuD regulates the translation and splicing of multiple Alzheimer's disease (AD) candidate genes. We generated ELAVL4 knockout (KO) human induced pluripotent stem cell-derived neurons to study the effect that ELAVL4 has on AD-related cellular phenotypes. ELAVL4 KO significantly increased the levels of specific APP isoforms and intracellular phosphorylated tau, molecular changes that are related to the pathological hallmarks of AD. Overexpression of ELAVL4 in wild-type neurons and rescue experiments in ELAVL4 KO cells showed opposite effects and also led to a reduction of the extracellular amyloid-beta (Aβ)42/40 ratio. All these observations were made in familial AD (fAD) and fAD-corrected neurons. To gain insight into the molecular cascades involved in neuronal ELAVL4 signaling, we conducted pathway and upstream regulator analyses of transcriptomic and proteomic data from the generated neurons. These analyses revealed that ELAVL4 affects multiple biological pathways linked to AD, including those involved in synaptic function, as well as gene expression downstream of APP and tau signaling. The analyses also suggest that ELAVL4 expression is regulated by insulin receptor-FOXO1 signaling in neurons. Taken together, ELAVL4 expression ameliorates AD-related molecular changes in neurons and affects multiple synaptic pathways, making it a promising target for novel drug development.
RNA 结合蛋白 ELAVL4/HuD 调节多种阿尔茨海默病（AD）候选基因的翻译和剪接。我们生成了 ELAVL4 敲除（KO）的人诱导多能干细胞源性神经元，以研究 ELAVL4 对 AD 相关细胞表型的影响。ELAVL4 KO 显著增加了特定 APP 异构体和细胞内磷酸化 tau 的水平，这些分子变化与 AD 的病理标志物有关。ELAVL4 在野生型神经元中的过表达和 ELAVL4 KO 细胞中的挽救实验显示出相反的效果，也导致细胞外淀粉样蛋白-β（Aβ）42/40 比值降低。所有这些观察结果都是在家族性 AD（fAD）和 fAD 校正神经元中进行的。为了深入了解神经元 ELAVL4 信号转导中涉及的分子级联反应，我们对生成的神经元的转录组和蛋白质组数据进行了途径和上游调节剂分析。这些分析表明，ELAVL4 影响与 AD 相关的多个生物学途径，包括与突触功能相关的途径，以及 APP 和 tau 信号下游的基因表达。分析还表明，神经元中 ELAVL4 的表达受胰岛素受体-FOXO1 信号的调节。总之，ELAVL4 的表达改善了神经元中与 AD 相关的分子变化，并影响了多个突触途径，使其成为开发新药物的有希望的靶点。
