Prozorovski Timour, Schulze-Topphoff Ulf, Glumm Robert, Baumgart Jan, Schröter Friederike, Ninnemann Olaf, Siegert Elise, Bendix Ivo, Brüstle Oliver, Nitsch Robert, Zipp Frauke, Aktas Orhan
Cecilie Vogt Clinic for Neurology in the Helios Klinikum Berlin-Buch, Charité - Universitätsmedizin Berlin, and Max Delbrück Center for Molecular Medicine, Charitéplatz 1, 10117 Berlin, Germany.
Nat Cell Biol. 2008 Apr;10(4):385-94. doi: 10.1038/ncb1700. Epub 2008 Mar 16.
Repair processes that are activated in response to neuronal injury, be it inflammatory, ischaemic, metabolic, traumatic or other cause, are characterized by a failure to replenish neurons and by astrogliosis. The underlying molecular pathways, however, are poorly understood. Here, we show that subtle alterations of the redox state, found in different brain pathologies, regulate the fate of mouse neural progenitor cells (NPCs) through the histone deacetylase (HDAC) Sirt1. Mild oxidation or direct activation of Sirt1 suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal lineage, whereas reducing conditions had the opposite effect. Under oxidative conditions in vitro and in vivo, Sirt1 was upregulated in NPCs, bound to the transcription factor Hes1 and subsequently inhibited pro-neuronal Mash1. In utero shRNA-mediated knockdown of Sirt1 in NPCs prevented oxidation-mediated suppression of neurogenesis and caused upregulation of Mash1 in vivo. Our results provide evidence for an as yet unknown metabolic master switch that determines the fate of neural progenitors.
响应神经元损伤而被激活的修复过程，无论是炎症性、缺血性、代谢性、创伤性还是其他原因引起的，其特征都是无法补充神经元以及星形胶质细胞增生。然而，其潜在的分子途径却知之甚少。在此，我们表明，在不同脑病理状态下发现的氧化还原状态的细微变化，通过组蛋白去乙酰化酶（HDAC）Sirt1调节小鼠神经祖细胞（NPC）的命运。Sirt1的轻度氧化或直接激活会抑制NPC的增殖，并使其分化偏向星形胶质细胞谱系，而以神经元谱系为代价，而还原条件则产生相反的效果。在体外和体内的氧化条件下，NPC中Sirt1上调，与转录因子Hes1结合，随后抑制促神经元因子Mash1。子宫内通过shRNA介导的NPC中Sirt1的敲低可防止氧化介导的神经发生抑制，并在体内导致Mash1上调。我们的结果为一个尚未知晓的代谢主开关提供了证据，该开关决定神经祖细胞的命运。
