Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing

Xiao-Ru Ma, Xudong Zhu, Yujie Xiao, Hui-Min Gu, Shuang-Shuang Zheng, Liang Li, Fan Wang, Zhao-Jun Dong, Di-Xian Wang, Yang Wu, Chenyu Yang, Wenhong Jiang, Ke Yao, Yue Yin, Yang Zhang, Chao Peng, Lixia Gao, Zhuoxian Meng, Zeping Hu, Chong Liu, Li Li, Hou-Zao Chen (), Yousheng Shu (), Zhenyu Ju () and Jing-Wei Zhao ()
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Xiao-Ru Ma: Zhejiang University School of Medicine
Xudong Zhu: Hangzhou Normal University
Yujie Xiao: Fudan University
Hui-Min Gu: Zhejiang University School of Medicine
Shuang-Shuang Zheng: Zhejiang University School of Medicine
Liang Li: Fudan University
Fan Wang: Zhejiang University School of Medicine
Zhao-Jun Dong: Zhejiang University School of Medicine
Di-Xian Wang: Zhejiang University School of Medicine
Yang Wu: Zhejiang University School of Medicine
Chenyu Yang: Zhejiang University
Wenhong Jiang: Zhejiang University School of Medicine
Ke Yao: Tsinghua University
Yue Yin: Shanghai Advanced Research Institute, Chinese Academy of Sciences
Yang Zhang: Zhongshan Hospital of Fudan University
Chao Peng: Shanghai Advanced Research Institute, Chinese Academy of Sciences
Lixia Gao: Zhejiang University School of Medicine
Zhuoxian Meng: Zhejiang University School of Medicine
Zeping Hu: Tsinghua University
Chong Liu: Zhejiang University School of Medicine
Li Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Hou-Zao Chen: Chinese Academy of Medical Sciences & Peking Union Medical College
Yousheng Shu: Beijing Normal University
Zhenyu Ju: Jinan University
Jing-Wei Zhao: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

Date: 2022
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DOI: 10.1038/s41467-022-28844-1

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