RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons.
RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons.
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DOI：
10.1016/j.pneurobio.2022.102316
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发表时间：
2022-10
影响因子：
6.7
通讯作者：
Poelmans, Geert
中科院分区：
文献类型：
--
作者：
van der Linden, Robert J.;Gerritsen, Jacqueline S.;Liao, Meichen;Widomska, Joanna;Pearse II, Richard V.;White, Forest M.;Franke, Barbara;Young-Pearse, Tracy L.;Poelmans, Geert
RNA结合蛋白ELAVL4/HUD调节多个阿尔茨海默病(AD)候选基因的翻译和剪接。我们建立了ELAVL4基因敲除(KO)人诱导的多能干细胞来源的神经元，以研究ELAVL4对AD相关细胞表型的影响。ELAVL4 KO可显著增加特定APP亚型和细胞内磷酸化tau的水平，这是与AD的病理特征相关的分子变化。在野生型神经元中过表达ELAVL4和在ELAVL4KO细胞中进行抢救实验显示了相反的效果，并导致细胞外淀粉样β蛋白(Aβ)42/40比值降低。所有这些观察都是在家族性AD(FAD)和FAD校正后的神经元上进行的。为了深入了解参与神经元ELAVL4信号转导的分子级联，我们对生成的神经元的转录和蛋白质组数据进行了路径和上游调节因子分析。这些分析表明，ELAVL4影响与AD相关的多个生物通路，包括那些参与突触功能的通路，以及APP和tau信号下游的基因表达。分析还表明，ELAVL4的表达受神经元中胰岛素受体-FOXO1信号的调节。综上所述，ELAVL4的表达改善了神经元中与AD相关的分子变化，影响了多条突触通路，使其成为新药开发的一个有前景的靶点。
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.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
14.9
作者：
Bolognani F;Contente-Cuomo T;Perrone-Bizzozero NI
通讯作者：
Perrone-Bizzozero NI
DOI：
10.3233/jad-2009-0967
发表时间：
2009
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Amadio M;Pascale A;Wang J;Ho L;Quattrone A;Gandy S;Haroutunian V;Racchi M;Pasinetti GM
通讯作者：
Pasinetti GM
影响因子：
48
作者：
Bonda, David J.;Lee, Hyoung-gon;Camins, Antoni;Pallas, Merce;Casadesus, Gemma;Smith, Mark A.;Zhu, Xiongwei
通讯作者：
Zhu, Xiongwei
影响因子：
19
作者：
Giannakou, ME;Partridge, L
通讯作者：
Partridge, L