Loss of β-catenin via activated GSK3β causes diabetic retinal neurodegeneration by instigating a vicious cycle of oxidative stress-driven mitochondrial impairment

Abstract

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.

Pregabalin Mediates Retinal Ganglion Cell Survival From Retinal Ischemia/Reperfusion Injury Via the Akt/GSK3β/β-Catenin Signaling Pathway

“…A previous study documented that abnormal GSK3β activation contributes to mitochondrial dysregulation in diabetic retinal neurodegeneration by inhibiting downstream β-catenin–regulated oxidative stress resistance. 26 In this study, we found a significant decrease in the phosphorylation of Akt (serine 473) and GSK3β (serine 9) in the retina following RIR ( Fig. 4 A), resulting in abnormal activation of GSK3β ( Fig.…”

GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target

“…For instance, the phosphorylation of GSK3β Ser9 is decreased in rat retinas by N-Methyl-N-nitrosourea (MNU) treatment, a well-established paradigm for inducible photoreceptor cell death [ 89 ], suggesting an increase in GSK3β activation [ 90 ]. In diabetic mice with DR, a positive correlation between GSK3 activation and retinal neuron apoptosis has also been reported [ 91 , 92 ]. Similarly, the levels of phosphorylated Ser21/9 in GSK3α/β are lower in a serum-deprived RGC cell line model [ 93 ].…”

“…Any minor changes in oxidative stress signaling as well as the increase of ROS levels can trigger retinal degeneration. In diabetic mice with DR, the increased activation of GSK3 was shown to lead to RGCs degeneration via increased mitochondrial oxidative stress [ 91 ]. In humans, increased oxidative stress has been demonstrated in AMD [ 115 ], DR [ 116 ], and RP [ 117 , 118 ].…”

“…Concerning RGC protection, the inhibition of GSK3 with small molecules showed a beneficial effect against cell death in diabetic mice with DR [ 91 , 92 , 211 , 212 ], and in the N-methyl-D-aspartate (NMDA) neurotoxicity model of mouse retinal explants [ 96 ]. The use of siRNA to knockdown GSK3β after rat optic nerve crush also suggested that GSK3 inhibition is neuroprotective for RGCs [ 213 ].…”

“…Indeed, using GSK3 inhibitors to modulate GSK3 activity should be finely regulated, depending on the disease and the disease’s stage. For the case of DR, GSK3 is reported as activated and its inhibition might be beneficial at the early stage of the disease to preserve RGCs [ 91 ] but then keeping GSK3 inactivated might promote VEGF expression and angiogenesis through downstream effectors of the Wnt pathway [ 172 , 173 , 174 ]. Along the same line, in AMD, GSK3 inhibition could be beneficial in the dry form when neovessels are absent, but deleterious in the wet form by promoting retinal neovascularization.…”