Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Nat Cell Biol. 2013 Jun;15(6):614-24. doi: 10.1038/ncb2735. Epub 2013 May 5.
Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis.
少突胶质细胞是中枢神经系统中形成髓鞘的细胞，在成年期可以再生。在成年人中，新的少突胶质细胞来源于少突胶质前体细胞（OPC），也来源于神经干细胞（NSC）。虽然已经鉴定出了几种支持少突胶质细胞产生的因子，但成年少突胶质细胞产生的机制在很大程度上仍不清楚。在这里，我们发现，一种与能量代谢有关的蛋白去乙酰化酶 SIRT1 的基因失活会增加成年小鼠大脑中 OPC 的产生，其部分作用机制是通过 NSC 发挥的。SIRT1 失活后产生的新 OPC 会正常分化，产生具有完整髓鞘的少突胶质细胞。值得注意的是，SIRT1 的失活会改善脱髓鞘损伤的小鼠模型中的髓鞘再生并延迟瘫痪。SIRT1 的失活会导致参与细胞代谢和生长因子信号转导的基因上调，特别是 PDGF 受体α（PDGFRα）。SIRT1 失活后少突胶质细胞的扩增至少部分是通过 PDGFRα 下游的 AKT 和 p38 MAPK 信号分子介导的。鉴定出可调控成年少突胶质细胞再生的药物靶标酶，可能有助于开发针对脱髓鞘损伤和多发性硬化症等疾病的治疗方法。
