Research Paper Volume 15, Issue 15 pp 7513—7532

LncRNA NORAD defects deteriorate the formation of age-related macular degeneration

Jinfeng Zhang1, , Jing Jiang1, , Hongyu Zhou1, , Shenjun Li2, , Weihua Bian1, , Lifu Hu2, , Daolai Zhang1, , Cong Xu1, , Yeying Sun1, ,

  • 1 College of Pharmacy, Binzhou Medical University, Shandong, China
  • 2 Non-Clinical Research Department, RemeGen Co., Ltd, Shandong, China

Received: December 14, 2022       Accepted: May 23, 2023       Published: July 29, 2023
How to Cite

Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Long noncoding RNAs (lncRNAs) play important roles in the development of age-related macular degeneration (AMD). However, the effect of long non-coding RNA activated by DNA damage (NORAD) on AMD remains unknown. This study aimed to investigate the effect of NORAD on RPE cell senescence and degeneration. Irradiated adult retinal pigment epithelial cell line-19 (ARPE-19) and sodium iodate-treated mice were used as in vitro and in vivo AMD models. Results showed that irradiation-induced AMD characteristics of ARPE-19 and NORAD-knockdown aggravated cell cycle arrest in the G2/M phase, cell apoptosis and cell senescence along with the increased expression of phosphorylated P53 (p-P53) and P21. AMD factors C3, ICAM-1, APP, APOE, and VEGF-A were also increased by NORAD-knockdown. Moreover, NORAD-knockdown increased irradiation-induced reduction of mitochondrial homeostasis factors, (i.e., TFAM and POLG) and mitochondrial respiratory chain complex genes (i.e., ND1 and ND5) along with mitochondrial reactive oxygen species (ROS). We also identified a strong interaction of NORAD and PGC-1α and sirtuin 1 (SIRT1) in ARPE-19; that is, NORAD knockdown increases the acetylation of PGC-1α. In NORAD knockout mice, NORAD-knockout accelerated the sodium iodate-reduced retinal thickness reduction, function impairment and loss of retinal pigment in the fundus. Therefore, NORAD-knockdown accelerates retinal cell senescence, apoptosis, and AMD markers via PGC-1α acetylation, mitochondrial ROS, and the p-P53–P21signaling pathway, in which NORAD-mediated effect on PGC-1α acetylation might occur through the direct interaction with PGC-1α and SIRT1.


NORAD: non-coding RNA activated by DNA damage; NORAD-KO or -/-: NORAD-knockout; SA-β-gal: senescence associated-beta-galactosidase; ROS: reactive oxygen species; siNORAD: small interfering RNA-targeting NORAD; siSIRT1: small interfering RNA-targeting SIRT1; siNC: small interfering RNA-targeting negative control; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SIRT1: sirtuin 1; C3: complement C3; ICAM-1: intercellular adhesion molecule 1; VEGFA: Vascular Endothelial Growth Factor A; APOE: apolipoprotein E; APP: amyloid beta precursor protein; Aβ-40: amyloid β-40; Aβ-42: amyloid β-42; CRYAA: crystallin alpha A.