Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, 310058, Hangzhou, Zhejiang, China.
Center of Cryo-Electron Microscopy, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
Nat Commun. 2023 Nov 17;14(1):7476. doi: 10.1038/s41467-023-43292-1.
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.
作为大脑中的主要神经元类型，兴奋性神经元（EN）调节秀丽隐杆线虫的寿命。然而，EN 如何获得衰老仍然未知。在这里，我们表明生长分化因子 11（GDF11）在成年小鼠、狨猴和人脑的 EN 中高度表达。在小鼠中，GDF11 在有丝分裂后 EN 中的选择性敲除会塑造与大脑衰老相关的转录特征，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，损害它们的物体识别记忆并缩短寿命，从而在 GDF11、大脑衰老和认知之间建立了功能联系。体外 GDF11 缺失会导致 Neuro-2a 细胞发生细胞衰老。在机制上，GDF11 通过 Smad2 诱导促衰老因子 p21 的转录诱导神经元衰老。这项工作表明，内源性 GDF11 是 EN 衰老和大脑衰老的制动因素。
