Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20057, USA.
Laboratory of Retinal Cell & Molecular Biology (HNW28), NIH/NEI, Bethesda, MD, 20814, USA.
Sci Rep. 2020 Feb 12;10(1):2464. doi: 10.1038/s41598-020-59244-4.
Age-related macular degeneration is a major cause of vision impairment in the Western world among people of 55 years and older. Recently we have shown that autophagy is dysfunctional in the retinal pigment epithelium (RPE) of the AMD donor eyes (AMD RPE). We also showed increased reactive oxygen (ROS) production, increased cytoplasmic glycogen accumulation, mitochondrial dysfunction and disintegration, and enlarged and annular LAMP-1-positive organelles in AMD RPE. However, the underlying mechanisms inducing these abnormalities remain to be elucidated. Here, by performing a comprehensive study, we show increased PAPR2 expression, deceased NAD+, and SIRT1, increased PGC-1α acetylation (inactive form), lower AMPK activity, and overactive mTOR pathway in AMD RPE as compared to normal RPE. Metabolomics and lipidomics revealed dysregulated metabolites in AMD RPE as compared to normal RPE, including glycerophospholipid metabolism, involved in autophagy, lipid, and protein metabolisms, glutathione, guanosine, and L-glutamic acid, which are implicated in protection against oxidative stress and neurotoxicity, further supporting our observations. Our data show dysregulated metabolic pathways as important contributors to AMD pathophysiology, and facilitate the development of new treatment strategies for this debilitating disease of the visual system.
年龄相关性黄斑变性是西方 55 岁及以上人群视力损害的主要原因。最近，我们发现 AMD 供体眼中的视网膜色素上皮（RPE）中的自噬功能失调。我们还发现 AMD RPE 中活性氧（ROS）产生增加、细胞质糖原积累增加、线粒体功能障碍和崩解、以及 Lamp-1 阳性细胞器增大和呈环形。然而，诱导这些异常的潜在机制仍有待阐明。在这里，通过进行全面研究，我们发现与正常 RPE 相比，AMD RPE 中的 PAPR2 表达增加、NAD+减少、SIRT1 减少、PGC-1α乙酰化（失活形式）增加、AMPK 活性降低和 mTOR 通路过度活跃。代谢组学和脂质组学显示与正常 RPE 相比，AMD RPE 中的代谢物失调，包括甘油磷脂代谢，涉及自噬、脂质和蛋白质代谢、谷胱甘肽、鸟苷和 L-谷氨酸，这些都与对抗氧化应激和神经毒性有关，进一步支持了我们的观察结果。我们的数据表明，代谢途径失调是 AMD 病理生理学的重要因素，并为这种使人衰弱的视觉系统疾病的新治疗策略的发展提供了依据。
