Research Paper Volume 12, Issue 13 pp 13437—13462
Loss of β-catenin via activated GSK3β causes diabetic retinal neurodegeneration by instigating a vicious cycle of oxidative stress-driven mitochondrial impairment
- 1 Department of Physiology, School of Basic Medical Sciences, Shenzhen University Health Sciences Center, Shenzhen, Guangdong, China
- 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
- 3 Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- 4 Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
Received: February 17, 2020 Accepted: April 28, 2020 Published: June 23, 2020https://doi.org/10.18632/aging.103446
How to Cite
Copyright © 2020 Shu 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.
Synaptic neurodegeneration of retinal ganglion cells (RGCs) is the earliest event in the pathogenesis of diabetic retinopathy. Our previous study proposed that impairment of mitochondrial trafficking by hyperphosphorylated tau is a potential contributor to RGCs synapse degeneration. However, other molecular mechanisms underlying mitochondrial defect in diabetic retinal neurodegeneration remain to be elucidated. Here, using a high-fat diet (HFD)-induced diabetic mouse model, we showed for the first time that downregulation of active β-catenin due to abnormal GSK3β activation caused synaptic neurodegeneration of RGCs by inhibiting ROS scavenging enzymes, thus triggering oxidative stress-driven mitochondrial impairment in HFD-induced diabetes. Rescue of β-catenin via ectopic expression of β-catenin with a recombinant adenoviral vector, or via GSK3β inhibition by a targeted si-GSK3β, through intravitreal administration, abrogated the oxidative stress-derived mitochondrial defect and synaptic neurodegeneration in diabetic RGCs. By contrast, ablation of β-catenin by si-β-catenin abolished the protective effect of GSK3β inhibition on diabetic RGCs by suppression of antioxidant scavengers and augmentation of oxidative stress-driven mitochondrial lesion. Thus, our data identify β-catenin as a part of an endogenous protective system in diabetic RGCs and a promising target to develop intervention strategies that protect RGCs from neurodegeneration at early onset of diabetic retinopathy.