The Mechanism of Endoplasmic Reticulum Proteostasis and Proteotoxicity in Retinal Degeneration

视网膜变性中内质网蛋白稳态和蛋白毒性的机制

• 批准号: 20K09819
• 负责人: CHIANG WeiChieh
• 金额: $ 2.66万
• 依托单位: Okinawa Institute of Science and Technology Graduate University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2020
• 资助国家: 日本
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20K09819/
• 关键词: ER stress; ER proteostasis; retina; Retinal Degeneration; Photoreceptor Cells; Protein Misfolding; ER Stress; Stress Response

ER membrane protein complex (EMC) is an important factor for ER homeostasis maintenance and membrane protein biogenesis. Using an EMC-deficient zebrafish model, I found that mutant fish display various retinal phenotypes, including the loss of photoreceptor cells and lack of visual function. Additionally, an EMC-deficient zebrafish carrying a reporter gene that monitor UPR activation in real time, I found that UPR is activated as early as 3 days post fertilization (dpf). This finding is further confirmed with bulk RNA sequencing analysis and qPCR analysis. These data suggest that ER stress and UPR may play a critical role in regulating retinal degeneration associated with EMC-dysfunction.

内质网膜蛋白复合物（EMC）是内质网稳态维持和膜蛋白生物发生的重要因素。使用 EMC 缺陷的斑马鱼模型，我发现突变鱼表现出各种视网膜表型，包括感光细胞丧失和视觉功能缺乏。此外，我发现，一只缺乏 EMC 的斑马鱼携带实时监测 UPR 激活的报告基因，UPR 最早在受精后 3 天 (dpf) 就被激活。大量 RNA 测序分析和 qPCR 分析进一步证实了这一发现。这些数据表明 ER 应激和 UPR 可能在调节与 EMC 功能障碍相关的视网膜变性中发挥关键作用。