Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis.
Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis.
复制标题
动态水通道蛋白-4亚细胞再定位在中枢神经系统水平衡中的新作用。
DOI：
10.1093/brain/awab311
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发表时间：
2022-03-29
期刊：
影响因子：
14.5
通讯作者：
Bill, Roslyn M.
中科院分区：
文献类型：
--
作者：
Salman, Mootaz M.;Kitchen, Philip;Halsey, Andrea;Wang, Marie Xun;Tornroth-Horsefield, Susanna;Conner, Alex C.;Badaut, Jerome;Iliff, Jeffrey J.;Bill, Roslyn M.
水通道蛋白通道促进水在所有细胞和组织中的双向流动。AQP 4在星形胶质细胞中高度表达。在CNS中，它富集在星形胶质细胞终足、突触和胶质界膜中，在那里它介导穿过血-脊髓和血-脑屏障（BSCB/BBB）的水交换，并控制细胞体积、细胞外空间体积和星形胶质细胞迁移。AQP 4在BSCB/BBB的血管周围富集表明在胶质淋巴功能中的作用。最近，我们已经证明，AQP 4定位也在亚细胞水平上动态调节，影响膜的水渗透性。衰老、脑血管疾病、创伤性CNS损伤和睡眠中断是发展神经变性的既定和新兴风险因素，并且在每种动物模型中，胶质淋巴功能受损与血管周围AQP 4定位的变化相关。CNS水肿是由响应于渗透压失衡而通过AQP 4的被动水内流引起的。我们已经证明，减少AQP 4到BSCB/BBB的动态再定位可以减少CNS水肿并加速啮齿动物模型的功能恢复。鉴于开发孔阻断AQP 4抑制剂的困难，靶向AQP 4亚细胞定位为CNS水肿、神经血管和神经退行性疾病开辟了新的治疗途径，并提供了一个框架来解决健康和疾病中有关水稳态的基本问题。
Aquaporin channels facilitate bidirectional water flow in all cells and tissues. AQP4 is highly expressed in astrocytes. In the CNS, it is enriched in astrocyte endfeet, at synapses, and at the glia limitans, where it mediates water exchange across the blood–spinal cord and blood–brain barriers (BSCB/BBB), and controls cell volume, extracellular space volume, and astrocyte migration. Perivascular enrichment of AQP4 at the BSCB/BBB suggests a role in glymphatic function. Recently, we have demonstrated that AQP4 localization is also dynamically regulated at the subcellular level, affecting membrane water permeability. Ageing, cerebrovascular disease, traumatic CNS injury, and sleep disruption are established and emerging risk factors in developing neurodegeneration, and in animal models of each, impairment of glymphatic function is associated with changes in perivascular AQP4 localization. CNS oedema is caused by passive water influx through AQP4 in response to osmotic imbalances. We have demonstrated that reducing dynamic relocalization of AQP4 to the BSCB/BBB reduces CNS oedema and accelerates functional recovery in rodent models. Given the difficulties in developing pore-blocking AQP4 inhibitors, targeting AQP4 subcellular localization opens up new treatment avenues for CNS oedema, neurovascular and neurodegenerative diseases, and provides a framework to address fundamental questions about water homeostasis in health and disease.
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