Hamilton Glaucoma Center and Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
Center for Research on Biological Systems, National Center for Microscopy and Imaging Research and Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
Cell Death Dis. 2018 Feb 19;9(3):285. doi: 10.1038/s41419-017-0171-8.
Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role. However, whether the activation of cyclic adenosine 3',5'-monophosphate (cAMP) signaling pathway is associated with astrocyte dysfunction in the ONH remains unknown. We report here that the cAMP/protein kinase A (PKA) pathway is critical to ONH astrocyte dysfunction, leading to caspase-3 activation and cell death via the AKT/Bim/Bax signaling pathway. Furthermore, elevated intracellular cAMP exacerbates vulnerability to oxidative stress in ONH astrocytes, and this may contribute to axonal damage in glaucomatous neurodegeneration. Inhibition of intracellular cAMP/PKA signaling activation protects ONH astrocytes by increasing AKT phosphorylation against oxidative stress. These results strongly indicate that activation of cAMP/PKA pathway has an important role in astrocyte dysfunction, and suggest that modulating cAMP/PKA pathway has therapeutic potential for glaucomatous ONH degeneration.
青光眼的特征是视网膜神经节细胞及其轴突进行性丧失，但伴随的神经退行性变的潜在生物学基础尚不清楚。越来越多的证据表明，视神经盘（ONH）内星形胶质细胞的结构和功能异常起作用。然而，cAMP 信号通路的激活是否与 ONH 星形胶质细胞功能障碍有关尚不清楚。我们在这里报告 cAMP/蛋白激酶 A (PKA) 通路对 ONH 星形胶质细胞功能障碍至关重要，通过 AKT/Bim/Bax 信号通路导致 caspase-3 激活和细胞死亡。此外，细胞内 cAMP 的升高加剧了 ONH 星形胶质细胞对氧化应激的易感性，这可能导致青光眼神经退行性变中的轴突损伤。抑制细胞内 cAMP/PKA 信号转导激活通过增加 AKT 磷酸化来保护 ONH 星形胶质细胞对抗氧化应激。这些结果强烈表明 cAMP/PKA 通路的激活在星形胶质细胞功能障碍中起重要作用，并表明调节 cAMP/PKA 通路对治疗青光眼性 ONH 变性具有潜在作用。
