PDF(Pubmed)
Abstract：
Glycophagy has evolved from an alternative glycogen degradation pathway into a multifaceted pivot to regulate cellular metabolic hemostasis in peripheral tissues. However, the pattern of glycophagy in the brain and its potential therapeutic impact on ischemic stroke remain unknown. Here, we observed that the dysfunction of astrocytic glycophagy was caused by the downregulation of the GABA type A receptor-associated protein like 1 (GABARAPL1) during reperfusion in ischemic stroke patients and mice. PI3K-Akt pathway activation is involved in driving GABARAPL1 downregulation during cerebral reperfusion. Moreover, glycophagy dysfunction-induced glucosamine deficiency suppresses the nuclear translocation of specificity protein 1 and TATA binding protein, the transcription factors for GABARAPL1, by decreasing their O-GlcNAcylation levels, and accordingly feedback inhibits GABARAPL1 in astrocytes during reperfusion. Restoring astrocytic glycophagy by overexpressing GABARAPL1 decreases DNA damage and oxidative injury in astrocytes and improves the survival of surrounding neurons during reperfusion. In addition, a hypocaloric diet in the acute phase after cerebral reperfusion can enhance astrocytic glycophagic flux and accelerate neurological recovery. In summary, glycophagy in the brain links autophagy, metabolism, and epigenetics together, and glycophagy dysfunction exacerbates reperfusion injury after ischemic stroke.
摘要：
糖食已从替代的糖原降解途径发展成为多方面的枢纽，以调节外周组织中的细胞代谢止血。然而,大脑中的糖吞噬模式及其对缺血性卒中的潜在治疗作用尚不清楚.这里,我们观察到星形胶质细胞糖吞噬功能障碍是由缺血性卒中患者和小鼠再灌注期间GABAA型受体相关蛋白样1(GABARAPL1)的下调引起的.PI3K-Akt通路激活涉及在脑再灌注期间驱动GABARAPL1下调。此外，糖吞噬功能障碍诱导的葡糖胺缺乏抑制特异性蛋白1和TATA结合蛋白的核易位，GABARAPL1的转录因子，通过降低其O-GlcNAcylation水平，因此，在再灌注过程中，反馈会抑制星形胶质细胞中的GABARAPL1。通过过表达GABARAPL1恢复星形胶质细胞糖吞噬减少星形胶质细胞的DNA损伤和氧化损伤，并改善再灌注期间周围神经元的存活。此外,脑再灌注后急性期的低热量饮食可以增强星形胶质细胞的糖化通量并加速神经恢复。总之,大脑中的糖吞噬连接自噬，新陈代谢，和表观遗传学在一起，糖吞噬功能障碍会加剧缺血性卒中后的再灌注损伤。
