Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
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Aswin Pyakurel1,2, Delphine Balmer2, Marc K Saba-El-Leil3
1Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.
Abstract:
Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects.
Insights
Extracellular signal-regulated kinase 1/2 (ERK1/2) is crucial for retinal pigment epithelium (RPE) health and visual function. Inhibiting ERK1/2 disrupts the visual cycle, leading to RPE disorganization and vision loss.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Extracellular signal-regulated kinase 1/2 (ERK1/2) activity is elevated in age-related macular degeneration (ARMD) patients' retinal pigment epithelium (RPE).
- ERK1/2 inhibitors are used in cancer therapy but have uncharacterized ocular side effects.
Purpose of the Study:
- To investigate the role of ERK1/2 in RPE cells.
- To understand the consequences of ERK1/2 pathway disruption in the retina.
Main Methods:
- Conditional disruption of Erk1 and Erk2 genes in mouse RPE.
- Analysis of RPE65 expression, retinoid levels, visual function, and retinal structure.
Main Results:
- Loss of ERK1/2 activity significantly decreased RPE65 expression and ocular retinoid levels.
- ERK1/2 disruption led to impaired visual function and rapid RPE cell disorganization.
- Retinal degeneration was observed following the loss of ERK1/2 activity.
Conclusions:
- The ERK1/2 pathway directly regulates the visual cycle and is critical for RPE and photoreceptor cell viability.
- Caution is advised regarding kinase inhibitor dosage to prevent ocular side effects in cancer and ARMD treatments.
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