Myelin is a multiple-layered structureformed by oligodendrocytes. The ensheathment of axons by myelin plays animportant role in both functional integrity and long-term survival of axons andthus regulates activity of the central nervous system (CNS). However, withageing, some myelin sheaths exhibit myelin ageing and even myelin degenerationtermed as demyelination, which is the key pathological feature of theautoimmune inflammatory diseases of CNS such as multiple sclerosis (MS) and anearly pathological hallmark of neurodegenerative diseases. Also, myelin repairtermed as remyelination by oligodendrocytes which are differentiated fromoligodendrocyte progenitor cells (OPCs) occurs throughout life. Unfortunately,with ageing, the efficiency of remyelination declines mainly due to the reducedcapacity of OPC differentiation. Therefore, identifying new molecular targetsin OPCs to rejuvenate the aged OPCs holds the key to promote remyelination.
Recently, the research group led by Prof.ZHAOJingwei at the Zhejiang University School of Medicine, in collaborationwith Prof. CHEN Houzao at Chinese Academy of Medical Sciences & PekingUnion Medical College, Prof. SHU Yousheng at Beijing Normal University, and JUZhenyu at Jinan University, published an article entitled “Restoring nuclearentry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelinationduring ageing” in the journal Nature Communications.
Firstly, the study showed that SIRT2 isexpressed in postnatal OPCs but the nuclear localization of SIRT2 in OPCsduring remyelination declines during ageing. Using SIRT2 knock mice they showedthat SIRT2 is critical for remyelination. Furthermore, the study revealed thatNAD+ was one of the top metabolites that significantly decreased in the agedOPCs obtained from telomerase deficiency early ageing mice. Elevating NAD+ byβ-NMN, the immediate precursor of NAD+, enhances SIRT2 nuclear entry in OPCsand promotes OPCs differentiation. They further showed that in vivoNAD+supplementation not only prevents but also treats the demyelination andenhances remyelination efficiency in the CNS of the aged mice to the level ofthe young mice both structurally and functionally, highlighting the therapeuticeffect of β-NMN on demyelination diseases in the old animals.
Finally, the study clearly dissected themolecular mechanisms underlying the effects of NAD+: aged OPCs are depleted inSIRT2 nuclear localization and have less NAD+. Supplementation of β-NMNelevates the NAD+ level, restores nuclear entry of SIRT2 in the aged OPCs anddeacetylates H3K18, thus suppressing the transcription of ID4 and furtherpromoting OPCs differentiation, and eventually delays myelin ageing in thenormal CNS and enhances myelin repair in the demyelinated aged CNS (See theSchematic Figure).
“Our work demonstratesthat β-NMN not only delays myelin ageing in normal, but also enhances myelinrepair in diseased conditions,” Dr. MA Xiaoru, one of the first authors, says.“This study found β-NMN as a new small molecule for myelin ageing, and moreimportantly, identified SIRT2 as a new target for oligodendrocyte lineagecells, paving the way for future clinical translation study on demyelinationand neurodegenerative diseases,” Prof. ZHAO Jingwei further states. 
The first author MA Xiaoru (middle in thefront line) and the corresponding author Prof. ZHAO Jingwei (front line, thefirst on the right) More information: PhD student MA Xiaoru(now postdoctoral fellow) and Prof. ZHU Xudong are the co-first authors of thisarticle. Prof. ZHAO Jingwei, Prof. JU Zhenyu, Prof. SHU Yousheng and Prof. CHEnHouzao are the co-corresponding authors of this article.
