Cell reports · 2023
Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zhang Hui, Li Jiaming, Yu Yang, Ren Jie, Liu Qiang, Bao Zhaoshi, Sun Shuhui, Liu Xiaoqian, Ma Shuai, Liu Zunpeng, Yan Kaowen, Wu Zeming, Fan Yanling, Sun Xiaoyan, Zhang Yixin, Ji Qianzhao, Cheng Fang, Wei Peng-Hu, Ma Xibo, Zhang Shiqiang, Xie Zhengwei, Niu Yuyu, Wang Yan-Jiang, Han Jing-Dong J, Jiang Tao, Zhao Guoguang, Ji Weizhi, Izpisua Belmonte Juan Carlos, Wang Si, Qu Jing, Zhang Weiqi, Liu Guang-Hui
Аннотация
The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using physiologically aged non-human primates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling encompassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro-inflammatory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons of aged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging in vitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons in vitro or oral administration to aged mice.