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Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration

  • Pyakurel, Aswin IRO, Institute for Research in Ophthalmology, Sion, Switzerland
  • Balmer, Delphine IRO, Institute for Research in Ophthalmology, Sion, Switzerland
  • Saba-El-Leil, Marc K. Institute for Research in Immunology and Cancer, Department of Pharmacology and Program of Molecular Biology, Université de Montréal, Montreal, Quebec, Canada
  • Kizilyaprak, Caroline Electron Microscopy Facility, University of Lausanne, Lausanne, Switzerland
  • Daraspe, Jean Electron Microscopy Facility, University of Lausanne, Lausanne, Switzerland
  • Humbel, Bruno M. Electron Microscopy Facility, University of Lausanne, Lausanne, Switzerland
  • Voisin, Laure Institute for Research in Immunology and Cancer, Department of Pharmacology and Program of Molecular Biology, Université de Montréal, Montreal, Quebec, Canada
  • Le, Yun Z. Department of Medicine Endocrinology and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  • von Lintig, Johannes Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
  • Meloche, Sylvain Institute for Research in Immunology and Cancer, Department of Pharmacology and Program of Molecular Biology, Université de Montréal, Montreal, Quebec, Canada
  • Roduit, Raphaël ORCID IRO, Institute for Research in Ophthalmology, Sion, Switzerland
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  • 2017-11-28
Published in:
  • Molecular and Cellular Biology. - American Society for Microbiology. - 2017, vol. 37, no. 24
Cell Biology
Molecular Biology
English 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.
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  • English
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hybrid
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https://sonar.ch/global/documents/145203
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