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Theranostics 2019; 9(4):1170-1180. doi:10.7150/thno.26281 This issue Cite

Research Paper

Abnormal mTORC1 signaling leads to retinal pigment epithelium degeneration

Jiancheng Huang^1,2,4*, Shun Gu^3*, Meng Chen^1,4*, Shu-jie Zhang^1,4*, Zhichun Jiang^5,6, Xue Chen², Chao Jiang², Guohua Liu⁷, Roxana A Radu^5,6, Xiantao Sun⁸, Douglas Vollrath⁹, Jianhai Du^10,11, Biao Yan^1,4✉, Chen Zhao^1,4✉

1. Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
2. Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China
3. Department of Ophthalmology, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
4. NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China
5. Stein Eye Institute, University of California, Los Angeles, CA, 90095
6. Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
7. Department of Ophthalmology, Qilu Children's Hospital of Shandong University, Jinan 250000, China
8. Department of Ophthalmology, Children's Hospital of Zheng Zhou, Zheng Zhou 450053, China
9. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
10. Department of Ophthalmology and Biochemistry, West Virginia University, Morgantown, West Virginia, USA
11. Department of Biochemistry, West Virginia University, Morgantown, WA 26505, USA
*These authors contributed equally to this work.

✉ Corresponding authors: Chen Zhao, MD, PhD. 83 Fenyang Road, Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University Shanghai 200031, China. Phone: +86(21)64377134 Fax: +86(21)64377151 E-mail: dr_zhaochencom. Biao Yan, PhD. 83 Fenyang Road, Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University Shanghai 200031, China. Phone: +86(21)64377134 Fax: +86(21)64377151 E-mail: yanbiao1982com More

Abstract

Retinal pigment epithelial (RPE) degeneration is potentially involved in the pathogenesis of several retinal degenerative diseases. mTORC1 signaling is shown as a crucial regulator of many biological processes and disease progression. In this study, we aimed at investigating the role of mTORC1 signaling in RPE degeneration.

Methods: Western blots were conducted to detect mTORC1 expression pattern during RPE degeneration. Cre-loxP system was used to generate RPE-specific mTORC1 activation mice. Fundus, immunofluorescence staining, transmission electron microscopy, and targeted metabolomic analysis were conducted to determine the effects of mTORC1 activation on RPE degeneration in vivo. Electroretinography, spectral-domain optical coherence tomography, and histological experiments were conducted to determine the effects of mTORC1 activation on choroidal and retinal function in vivo.

Results: RPE-specific activation of mTORC1 led to RPE degeneration as shown by the loss of RPE-specific marker, compromised cell junction integrity, and intracellular accumulation of lipid droplets. RPE degeneration further led to abnormal choroidal and retinal function. The inhibition of mTORC1 signaling with rapamycin could partially reverse RPE degeneration. Targeted metabolomics analysis further revealed that mTORC1 activation affected the metabolism of purine, carboxylic acid, and niacin in RPE.

Conclusion: This study revealed that abnormal activation of mTORC1 signaling leads to RPE degeneration, which could provide a promising target for the treatment of RPE dysfunction-related diseases.

Keywords: RPE degeneration, mTORC1, metabolism

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