eIF2α incites photoreceptor cell and retina damage by all-trans-retinal.

Apr 10, 2023

Experts: Danxue He,Lei Tao,Binxiang Cai,Xiangjun Chen,Yan Wang,Shiying Li,Chunyan Liao,Yuling Chen,Jingmeng Chen,Zuguo Liu,Yalin Wu

Dry age-related macular degeneration (AMD) and recessive Stargardt’s disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal (atRAL) induced by chaos in visual cycle is closely associated with retinal atrophy in dry AMD and STGD1, but its critical downstream signaling molecules remain ambiguous. Here, we reported that activation of eukaryotic translation initiation factor 2α (eIF2α) by atRAL promoted retinal degeneration and photoreceptor loss through activating c-Jun N-terminal kinase (JNK) signaling-dependent apoptosis and gasdermin E (GSDME)-mediated pyroptosis. We determined that eIF2α activation by atRAL in photoreceptor cells resulted from endoplasmic reticulum (ER) homeostasis disruption caused at least in part by reactive oxygen species (ROS) production, and it activated JNK signaling independent of and dependent on activating transcription factor 4 (ATF4) and the ATF4/transcription factor C/EBP homologous protein (CHOP) axis. CHOP overexpression induced apoptosis of atRAL-loaded photoreceptor cells through activating JNK signaling rather than inhibiting the expression of anti-apoptotic gene Bcl2. JNK activation by eIF2α facilitated photoreceptor cell apoptosis caused by atRAL via caspase-3 activation and DNA damage. Additionally, we demonstrated that eIF2α was activated in neural retina of light-exposed Abca4Rdh8 mice, a model that shows severe defects in atRAL clearance and displays primary features of human dry AMD and STGD1. Of note, inhibition of eIF2α activation by salubrinal effectively ameliorated retinal degeneration and photoreceptor apoptosis in Abca4Rdh8 mice upon light exposure. The results of this study suggest that eIF2α is an important target to develop drug therapies for the treatment of dry AMD and STGD1.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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ABOUT THE EXPERTS

Danxue He,Lei Tao,Binxiang Cai,Xiangjun Chen,Yan Wang,Shiying Li,Chunyan Liao,Yuling Chen,Jingmeng Chen,Zuguo Liu,Yalin Wu

Danxue He

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Lei Tao

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Binxiang Cai

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Xiangjun Chen

Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, 268 Kaixuan Road, Hangzhou, China.

Yan Wang

Department of Ophthalmology, South China Hospital, Medical School, Shenzhen University, Shenzhen, China.

Shiying Li

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Chunyan Liao

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Yuling Chen

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Jingmeng Chen

School of Medicine, Xiamen University, Xiamen, China.

Zuguo Liu

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. Electronic address: zuguoliu@xmu.edu.cn.

Yalin Wu

Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Shenzhen Research Institute of Xiamen University, Shenzhen, China; Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. Electronic address: yalinw@xmu.edu.cn.