Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer's disease and aging.
Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer's disease and aging.
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生存基因消除诱导的死亡（DISE）与阿尔茨海默病和衰老中的神经毒性相关。
DOI：
10.1038/s41467-023-44465-8
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发表时间：
2024-01-18
影响因子：
16.6
通讯作者：
Peter, Marcus E
中科院分区：
文献类型：
--
作者：
Paudel, Bidur;Jeong, Si-Yeon;Martinez, Carolina Pena;Rickman, Alexis;Haluck-Kangas, Ashley;Bartom, Elizabeth T;Fredriksen, Kristina;Affaneh, Amira;Kessler, John A;Mazzulli, Joseph R;Murmann, Andrea E;Rogalski, Emily;Geula, Changiz;Ferreira, Adriana;Heckmann, Bradlee L;Green, Douglas R;Sadleir, Katherine R;Vassar, Robert;Peter, Marcus E
阿尔茨海默病（AD）的特点是进行性神经退行性变，但导致细胞死亡的具体事件仍然知之甚少。生存基因消除诱导死亡（DISE）是一种由短rna通过rna诱导沉默复合体（RISC）介导的细胞死亡机制。因此，DISE是RNA干扰的一种形式，其中sRNAs（位置2-7）中富含g - 6mer种子序列靶向细胞生存必需基因中数百个富含c - 6mer种子匹配，导致细胞死亡途径的激活。在这里，我们使用Argonaute沉淀和RNAseq （Ago-RP-Seq）分析了risc结合的sRNAs，以量化几种模型系统中的6mer种子毒性。在小鼠AD模型和老化的大脑中，在来自AD患者的诱导多能干细胞来源的神经元中，以及在暴露于a β42寡聚物的细胞中，与对照相比，risc结合的sRNAs显示出向毒性更强的6mer种子的转变。相比之下，在80岁以上的“超级老人”（superager）的大脑中，与risc结合的srna被转移到更无毒的6 - mer种子中。缺乏无毒rna的细胞对a β42诱导的细胞死亡敏感，重新引入无毒rna具有保护作用。总之，DISE和Aβ42毒性之间的相关性表明，增加大脑中无毒mirna的水平或阻断有毒risc结合srna的活性可以改善神经退行性变。阿尔茨海默病（AD）中导致神经元死亡的事件尚不清楚。在这里，作者提供了RNA干扰在AD中的作用的证据。短rna引起神经毒性和DNA损伤见于AD和老年大脑，并被无毒rna抵消。
Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA-induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways. Here, using Argonaute precipitation and RNAseq (Ago-RP-Seq), we analyze RISC-bound sRNAs to quantify 6mer seed toxicity in several model systems. In mouse AD models and aging brain, in induced pluripotent stem cell-derived neurons from AD patients, and in cells exposed to Aβ42 oligomers, RISC-bound sRNAs show a shift to more toxic 6mer seeds compared to controls. In contrast, in brains of “SuperAgers”, humans over age 80 who have superior memory performance, RISC-bound sRNAs are shifted to more nontoxic 6mer seeds. Cells depleted of nontoxic sRNAs are sensitized to Aβ42-induced cell death, and reintroducing nontoxic RNAs is protective. Altogether, the correlation between DISE and Aβ42 toxicity suggests that increasing the levels of nontoxic miRNAs in the brain or blocking the activity of toxic RISC-bound sRNAs could ameliorate neurodegeneration. Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
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影响因子：
3.3
作者：
Lang, A. E.;Methner, D. N. Riherd;Ferreira, A.
通讯作者：
Ferreira, A.
影响因子：
4.6
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Patel M;Bartom ET;Paudel B;Kocherginsky M;O'Shea KL;Murmann AE;Peter ME
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4.3
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影响因子：
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作者：
Hafner, Markus;Renwick, Neil;Farazi, Thalia A.;Mihailovic, Aleksandra;Pena, John T. G.;Tuschl, Thomas
通讯作者：
Tuschl, Thomas
影响因子：
4.2
作者：
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