GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.
GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.
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DOI：
10.1038/s41467-023-43292-1
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发表时间：
2023-11-17
影响因子：
16.6
通讯作者：
Zhao, Jing-Wei
中科院分区：
文献类型：
--
作者：
Wang, Di-Xian;Dong, Zhao-Jun;Deng, Sui-Xin;Tian, Ying-Ming;Xiao, Yu-Jie;Li, Xinran;Ma, Xiao-Ru;Li, Liang;Li, Pengxiao;Chang, Hui-Zhong;Liu, Longqi;Wang, Fan;Wu, Yang;Gao, Xiang;Zheng, Shuang-Shuang;Gu, Hui-Min;Zhang, Ya-Nan;Wu, Jian-Bin;Wu, Fan;Peng, Yonglin;Zhang, Xiao-Wen;Zhan, Ren-Ya;Gao, Li-Xia;Sun, Qiming;Guo, Xing;Zhao, Xiao-Dong;Luo, Jian-Hong;Zhou, Ruhong;Han, Lei;Shu, Yousheng;Zhao, Jing-Wei
兴奋性神经元（excitatory neuron，EN）是脑内主要的神经元类型，对C.优雅的然而，EN如何获得衰老尚不清楚。在这里，我们表明，生长分化因子11（GDF 11）主要表达在EN在成年小鼠，绒猴和人脑。在小鼠中，有丝分裂后EN中GDF 11的选择性敲除塑造了脑衰老相关的转录谱，诱导EN衰老和过度兴奋，修剪它们的树突，阻碍它们的突触输入，损害物体识别记忆并缩短寿命，建立了GDF 11，脑衰老和认知之间的功能联系。体外GDF 11缺失导致Neuro-2a细胞中的细胞衰老。从机制上讲，GDF 11缺失通过Smad 2诱导的促衰老因子p21的转录诱导神经元衰老。这项工作表明内源性GDF 11对EN衰老和脑老化起制动作用。兴奋性神经元（EN）如何获得衰老尚不清楚。在这里，作者表明，EN中的GDF 11减缓了EN衰老，大脑老化，认知下降并维持寿命，揭示了EN衰老和大脑老化的潜在机制。
As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing. How excitatory neurons (EN) acquire senescence is unclear. Here, the authors show that GDF11 in ENs slows EN senescence, brain ageing, cognitive decline and maintains lifespan, revealing a mechanism underlying EN senescence and brain ageing.
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