The mechanistic target of rapamycin (mTOR) is assembled into signaling complexes of mTORC1 or mTORC2, and plays key roles in cell metabolism, stress response, and nutrient and growth factor sensing. Accumulating evidence from human and animal model studies has demonstrated a pathogenic role of hyperactive mTORC1 in age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) is a primary injury site in AMD. In mouse models of RPE-specific deletion of Tuberous sclerosis 1 ( Tsc1 ), which encodes an upstream suppressor of mTORC1, the hyperactivated mTORC1 metabolically reprogrammed the RPE and led to the degeneration of the outer retina and choroid (CH). In the current study, we use single-cell RNA sequencing (scRNA-seq) to identify an RPE mTORC1 downstream protein, dopamine- and cyclic AMP-regulated phosphoprotein of molecular weight 32,000 (DARPP-32). DARPP-32 was not found in healthy RPE but localized to drusen and basal linear deposits in human AMD eyes. In animal models, overexpressing DARPP-32 by adeno-associated virus (AAV) led to abnormal RPE structure and function. The data indicate that DARPP-32 is a previously unidentified signaling protein subjected to mTORC1 regulation and may contribute to RPE degeneration in AMD.

中文翻译：

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DARPP32，视网膜色素上皮中过度活跃的 mTORC1 的靶标

雷帕霉素 (mTOR) 的机制靶标被组装成 mTORC1 或 mTORC2 的信号复合物，并在细胞代谢、应激反应以及营养和生长因子传感中发挥关键作用。从人类和动物模型研究中积累的证据表明，过度活跃的 mTORC1 在年龄相关性黄斑变性 (AMD) 中具有致病作用。视网膜色素上皮细胞 (RPE) 是 AMD 的主要损伤部位。在 RPE 特异性缺失结节性硬化症 1 的小鼠模型中（TSC1)，它编码 mTORC1 的上游抑制因子，超活化的 mTORC1 代谢重编程 RPE 并导致外视网膜和脉络膜 (CH) 退化。在当前的研究中，我们使用单细胞 RNA 测序 (scRNA-seq) 鉴定 RPE mTORC1 下游蛋白、多巴胺和环 AMP 调节的分子量为 32,000 的磷蛋白 (DARPP-32)。DARPP-32 在健康的 RPE 中未发现，但定位于人类 AMD 眼中的玻璃膜疣和基底线状沉积物。在动物模型中，腺相关病毒 (AAV) 过表达 DARPP-32 会导致 RPE 结构和功能异常。数据表明 DARPP-32 是一种先前未被识别的信号蛋白，受 mTORC1 调控，可能导致 AMD 中的 RPE 退化。