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Electroporation-Based Genetic Modification of Primary Human Pigment Epithelial Cells Using the Sleeping Beauty Transposon System
Published on: February 4, 2021
Regulation of posttranscriptional modification as a possible therapeutic approach for retinal neuroprotection
Yoko Ozawa1, Toshihide Kurihara, Kazuo Tsubota
1Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Abstract:
Understanding pathogenesis at the molecular level is the first step toward developing new therapeutic approaches. Here, we review the molecular mechanisms of visual dysfunction in two common diseases, innate chorioretinal inflammation and diabetic retinopathy, and the role of the ubiquitin-proteasome system (UPS) in both processes. In innate chorioretinal inflammation, interleukin-6 family ligands induce STAT3 activation in photoreceptors, which causes UPS-mediated excessive degradation of the visual substance, rhodopsin. In diabetic retinopathy, angiotensin II type 1 receptor (AT1R) signaling activates ERK in the inner layers of the retina, causing UPS-mediated excessive degradation of the synaptic vesicle protein, synaptophysin. This latter effect may decrease synaptic activity, in turn adversely affecting neuronal survival. Both mechanisms involve increased UPS activity and the subsequent excessive degradation of a protein required for visual function. Finally, we review the therapeutic potential of regulating the UPS to protect tissue function, citing examples from clinical applications in other medical fields.
Insights
The ubiquitin-proteasome system (UPS) drives visual dysfunction in chorioretinal inflammation and diabetic retinopathy by degrading essential proteins like rhodopsin and synaptophysin. Modulating the UPS offers therapeutic potential for vision disorders.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cellular Biology
Background:
- Visual dysfunction arises from complex molecular pathways in diseases like innate chorioretinal inflammation and diabetic retinopathy.
- The ubiquitin-proteasome system (UPS) plays a critical role in cellular protein degradation and homeostasis.
Purpose of the Study:
- To review the molecular mechanisms underlying visual dysfunction in innate chorioretinal inflammation and diabetic retinopathy.
- To elucidate the specific roles of the UPS in these disease processes.
- To explore the therapeutic potential of targeting the UPS for vision protection.
Main Methods:
- Review of existing literature on molecular pathogenesis of chorioretinal inflammation and diabetic retinopathy.
- Analysis of the involvement of the ubiquitin-proteasome system (UPS) in protein degradation pathways.
- Examination of signaling cascades including STAT3, interleukin-6, AT1R, and ERK.
Main Results:
- In chorioretinal inflammation, STAT3 activation leads to UPS-mediated degradation of rhodopsin in photoreceptors.
- In diabetic retinopathy, AT1R signaling results in UPS-mediated degradation of synaptophysin in retinal neurons, potentially impairing synaptic function and neuronal survival.
- Both conditions exhibit increased UPS activity causing excessive degradation of crucial proteins for visual function.
Conclusions:
- The UPS is a key mediator of molecular pathogenesis in both innate chorioretinal inflammation and diabetic retinopathy.
- Targeting UPS activity presents a promising therapeutic strategy for preserving visual function in these debilitating eye diseases.
- Further research into UPS regulation could lead to novel treatments for various retinal disorders.
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