Department of Ophthalmology and Biomedical Genetics, University of Rochester Medical School, Rochester, NY 14642, USA.
Adv Exp Med Biol. 2010;664:403-9. doi: 10.1007/978-1-4419-1399-9_46.
Age-related macular degeneration (AMD) is a multi-factorial disease and a leading cause of blindness. Proteomic and genetic data suggest that activation or de-repression of the alternate complement cascade of innate immunity is involved in end-stage disease. Several lines of evidence suggest that production of reactive oxygen species and chronic oxidative stress lead to protein and lipid modifications that initiate the complement cascade. Understanding the triggers of these pathogenic pathways and the site of the primary insult will be important for development of targeted therapeutics. Endoplasmic reticulum (ER) stress from misfolded mutant proteins and other sources are an important potential tributary mechanism. We propose that misfolded-protein-induced ER stress in the retinal-pigmented epithelium and/or choroid could lead to chronic oxidative stress, complement deregulation and AMD. Small molecules targeted to ER stress and oxidative stress could allow for a shift from disease treatment to disease prevention.
年龄相关性黄斑变性（AMD）是一种多因素疾病，也是导致失明的主要原因。蛋白质组学和遗传学数据表明，先天免疫的替代补体级联的激活或去抑制与终末期疾病有关。有几条证据表明，活性氧的产生和慢性氧化应激导致起始补体级联的蛋白质和脂质修饰。了解这些致病途径的触发因素和主要损伤部位对于开发靶向治疗药物非常重要。来自错误折叠突变蛋白和其他来源的内质网（ER）应激是一个重要的潜在分支机制。我们提出，视网膜色素上皮和/或脉络膜中错误折叠蛋白引起的 ER 应激可能导致慢性氧化应激、补体失调和 AMD。针对 ER 应激和氧化应激的小分子药物可能使疾病的治疗转向预防。
