Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @Caen-Normandie (BB@C), GIP Cyceron, Normandy University, UNICAEN, INSERM, UMR-S U1237, Caen, France.
Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
Autophagy. 2022 Jun;18(6):1297-1317. doi: 10.1080/15548627.2021.1973339. Epub 2021 Sep 14.
Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two models of hypoxia reperfusion and an model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both and . We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation. AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGD: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.
脑缺血是涉及细胞机制级联反应的病理学，导致蛋白质稳态失调，包括巨自噬/自噬，最终导致神经元死亡。虽然现在已经接受脑缺血诱导自噬，但溶栓/能量恢复对蛋白质稳态的影响尚不清楚。在这里，我们研究了 PLAT/tPA（纤溶酶原激活物，组织）溶栓对自噬和神经元死亡的影响。在缺氧再灌注的两种模型和 PLAT/tPA 溶栓的血栓栓塞性中风模型中，我们发现缺血增强了神经元的有害自噬。有趣的是，PLAT/tPA 通过调节 PI3K-AKT-MTOR 通路来减少自噬，从而介导神经保护作用。我们发现 IGF1R（胰岛素样生长因子 I 受体；一种酪氨酸激酶受体）是有效的受体，并显示在人和中风患者中，PLAT/tPA 能够降解 IGFBP3（胰岛素样生长因子结合蛋白 3）以增加 IGF1（胰岛素样生长因子 1）的生物利用度，从而激活 IGF1R。AKT/蛋白激酶 B：胸腺瘤病毒原癌基因 1；EGFR：表皮生长因子受体；Hx：缺氧；IGF1：胰岛素样生长因子 1；IGF1R：胰岛素样生长因子 I 受体；IGFBP3：胰岛素样生长因子结合蛋白 3；Ka：红藻氨酸；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MAPK/ERK：丝裂原活化蛋白激酶；MTOR：雷帕霉素靶蛋白激酶；MTORC1：MTOR 复合物 1；OGD：氧葡萄糖剥夺；OGD：氧葡萄糖剥夺+再氧化；PepA：胃蛋白酶抑制剂 A1；PI3K：磷酸肌醇 3-激酶；PLAT/tPA：纤溶酶原激活物，组织；PPP：苦鬼白毒素；SCH77：SCH772984；ULK1：UNC-51 样激酶 1；Wort：wortmannin。
