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Redox regulation of PDE6 and cGMP signaling in diabetic retinal neurodegeneration
Cinthia Jhovanna Perez-Martinez1, Lidianys Maria Lewis-Luján1, Carlos Alexis Cota-Arrayales2
1Department of Biological Chemical Sciences. Sonora University, Blvd. Luis Encinas, Col. Centro, Hermosillo, Sonora, C.P. 83000, Mexico.
Abstract:
Diabetic retinal neurodegeneration is increasingly recognized as an early and critical component of diabetic retinopathy, driven in part by persistent oxidative stress and dysregulated intracellular signaling. Among these pathways, cyclic guanosine monophosphate (cGMP) signaling plays a central role in photoreceptor function and survival. Phosphodiesterase 6 (PDE6), the key enzyme responsible for cGMP hydrolysis in photoreceptors, has been extensively studied in inherited retinal disorders; however, its regulation under diabetic and redox-imbalanced conditions remains insufficiently defined. In this review, we examine the emerging role of redox imbalance in modulating PDE6 activity and stability in the diabetic retina. We discuss how mitochondrial and non-mitochondrial sources of reactive oxygen species (ROS) may disrupt PDE6 through proteostasis-related mechanisms involving AIPL1-dependent maturation and FAT10-mediated degradation. These alterations may lead to cGMP dysregulation, impaired ion channel activity, calcium imbalance, and photoreceptor dysfunction. We propose that PDE6-cGMP signaling represents a redox-sensitive hub linking oxidative stress to early neuronal damage in diabetic retinopathy. This mechanistic framework highlights PDE6 as a potential molecular target and supports the development of redox-based strategies aimed at preserving retinal function and preventing neurodegeneration.
Insights
Diabetic retinopathy causes early retinal neurodegeneration linked to oxidative stress. This review explores how redox imbalance affects Phosphodiesterase 6 (PDE6), a key enzyme, impacting cyclic guanosine monophosphate (cGMP) signaling and photoreceptor function.
Area of Science:
- Ophthalmology
- Neuroscience
- Biochemistry
Background:
- Diabetic retinopathy involves early retinal neurodegeneration.
- Oxidative stress and altered intracellular signaling are key drivers.
- Cyclic guanosine monophosphate (cGMP) signaling is vital for photoreceptor health.
Purpose of the Study:
- To review the role of redox imbalance in modulating Phosphodiesterase 6 (PDE6) activity and stability in the diabetic retina.
- To elucidate the mechanisms by which reactive oxygen species (ROS) affect PDE6.
- To highlight PDE6 as a potential therapeutic target for diabetic retinopathy.
Main Methods:
- Literature review focusing on PDE6 regulation under diabetic and oxidative stress conditions.
- Examination of proteostasis mechanisms (AIPL1-dependent maturation, FAT10-mediated degradation) affecting PDE6.
- Analysis of the link between PDE6 dysfunction, cGMP dysregulation, and photoreceptor damage.
Main Results:
- Redox imbalance, from mitochondrial and non-mitochondrial ROS sources, disrupts PDE6.
- Proteostasis pathways involving AIPL1 and FAT10 are implicated in PDE6 modulation.
- PDE6 alterations lead to cGMP dysregulation, ion channel dysfunction, and photoreceptor impairment.
Conclusions:
- PDE6-cGMP signaling is a redox-sensitive pathway connecting oxidative stress to neurodegeneration in diabetic retinopathy.
- Targeting PDE6 may offer a strategy to preserve retinal function and prevent neuronal damage.
- Further research into redox-based therapies for diabetic retinopathy is warranted.
