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

Xiao-Ru Ma,Wenhong Jiang,Yang Wu,Xudong Zhu,Zhao-Jun Dong,Clayton S.-C Yang ,Lixia Gao,Yujie Xiao,Yousheng Shu,Li Li,Huimin Gu ,Chao Peng,Yang Zhang,Hou-Zao Chen,Zhuo-Xian Meng ,Ke Yao,Chong Liu,Yue Yin,Fan Wang,Liang Li,Di-Xian Wang,Zhenyu Ju,Shuangshuang Zheng ,Zeping Hu,J W Zhao

doi:10.1038/s41467-022-28844-1

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.

Highlights

1234567890():,; 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)
Our results indicate that Sirtuin 2 (SIRT2) is expressed in postnatal OPCs, and its expression pattern switches from nucleus-containing in the majority of OPCs during myelin development to exclusively cytoplasmic in mature oligodendrocytes
The transcriptome database provided by Cahoy et al and Zhang et al revealed that the mRNA of SIRT2 is enriched in oligodendrocytes lineage cells[45,46]

Summary

Introduction

1234567890():,; 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. 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. With ageing, the efficiency of remyelination declines mainly due to the reduced capacity of OPC differentiation[17–21]. Such decline leads to disability in MS18, whose course usually spans several decades and progresses with ageing[22]. Identifying new molecular targets in OPC to rejuvenate the aged OPC holds much promise for this unmet medical need

Methods

Results

Conclusion