GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.

Autor: Wang DX; 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., Dong ZJ; 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., Deng SX; Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, 201508, Shanghai, China., Tian YM; BGI Research, 310030, Hangzhou, China., Xiao YJ; Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, 201508, Shanghai, China., Li X; The Global Scientific and Technological Innovation Center and the MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, 310058, Hangzhou, Zhejiang, China., Ma XR; 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., Li L; Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, 201508, Shanghai, China., Li P; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University, 200240, Shanghai, China., Chang HZ; BGI Research, 310030, Hangzhou, China., Liu L; BGI Research, 310030, Hangzhou, China., Wang F; 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., Wu Y; 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., Gao X; 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., Zheng SS; 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., Gu HM; 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., Zhang YN; Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China., Wu JB; 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., Wu F; Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, 310003, Hangzhou, China., Peng Y; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University, 200240, Shanghai, China., Zhang XW; 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., Zhan RY; Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, 310003, Hangzhou, China., Gao LX; Department of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, 310020, Hangzhou, China., Sun Q; Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Guo X; Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China., Zhao XD; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University, 200240, Shanghai, China., Luo JH; Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 310058, Hangzhou, Zhejiang, China.; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China., Zhou R; Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou, China., Han L; BGI Research, 310030, Hangzhou, China. hanlei2@genomics.cn., Shu Y; Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, 201508, Shanghai, China. yousheng@fudan.edu.cn., Zhao JW; 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. jingweizhao@zju.edu.cn.; Center of Cryo-Electron Microscopy, Zhejiang University, 310058, Hangzhou, Zhejiang, China. jingweizhao@zju.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 17; Vol. 14 (1), pp. 7476. Date of Electronic Publication: 2023 Nov 17.
DOI: 10.1038/s41467-023-43292-1
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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