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The Phosphoproteome of the Rd1 Mouse Retina, a Model of Inherited Photoreceptor Degeneration, Changes after Protein Kinase G Inhibition

Zhou, Jiaming LU ; Welinder, Charlotte LU and Ekström, Per LU (2023) In International Journal of Molecular Sciences 24(12).
Abstract

Retinitis pigmentosa (RP) is a frequent cause of blindness among the working population in industrial countries due to the inheritable death of photoreceptors. Though gene therapy was recently approved for mutations in the RPE65 gene, there is in general no effective treatment presently. Previously, abnormally high levels of cGMP and overactivation of its dependent protein kinase (PKG) have been suggested as causative for the fatal effects on photoreceptors, making it meaningful to explore the cGMP-PKG downstream signaling for more pathological insights and novel therapeutic target development purposes. Here, we manipulated the cGMP-PKG system in degenerating retinas from the rd1 mouse model pharmacologically via adding a PKG inhibitory... (More)

Retinitis pigmentosa (RP) is a frequent cause of blindness among the working population in industrial countries due to the inheritable death of photoreceptors. Though gene therapy was recently approved for mutations in the RPE65 gene, there is in general no effective treatment presently. Previously, abnormally high levels of cGMP and overactivation of its dependent protein kinase (PKG) have been suggested as causative for the fatal effects on photoreceptors, making it meaningful to explore the cGMP-PKG downstream signaling for more pathological insights and novel therapeutic target development purposes. Here, we manipulated the cGMP-PKG system in degenerating retinas from the rd1 mouse model pharmacologically via adding a PKG inhibitory cGMP-analogue to organotypic retinal explant cultures. A combination of phosphorylated peptide enrichment and mass spectrometry was then applied to study the cGMP-PKG-dependent phosphoproteome. We identified a host of novel potential cGMP-PKG downstream substrates and related kinases using this approach and selected the RAF1 protein, which may act as both a substrate and a kinase, for further validation. This showed that the RAS/RAF1/MAPK/ERK pathway may be involved in retinal degeneration in a yet unclarified mechanism, thus deserving further investigation in the future.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
mass spectrometry, organotypic retinal explant culture, phosphoproteome, retinal degeneration
in
International Journal of Molecular Sciences
volume
24
issue
12
article number
9836
publisher
MDPI AG
external identifiers
  • pmid:37372984
  • scopus:85163987785
ISSN
1661-6596
DOI
10.3390/ijms24129836
language
English
LU publication?
yes
id
ba5d244b-75c9-4dc0-958b-622c1bdefe47
date added to LUP
2023-09-15 14:24:48
date last changed
2024-04-19 00:58:06
@article{ba5d244b-75c9-4dc0-958b-622c1bdefe47,
  abstract     = {{<p>Retinitis pigmentosa (RP) is a frequent cause of blindness among the working population in industrial countries due to the inheritable death of photoreceptors. Though gene therapy was recently approved for mutations in the RPE65 gene, there is in general no effective treatment presently. Previously, abnormally high levels of cGMP and overactivation of its dependent protein kinase (PKG) have been suggested as causative for the fatal effects on photoreceptors, making it meaningful to explore the cGMP-PKG downstream signaling for more pathological insights and novel therapeutic target development purposes. Here, we manipulated the cGMP-PKG system in degenerating retinas from the rd1 mouse model pharmacologically via adding a PKG inhibitory cGMP-analogue to organotypic retinal explant cultures. A combination of phosphorylated peptide enrichment and mass spectrometry was then applied to study the cGMP-PKG-dependent phosphoproteome. We identified a host of novel potential cGMP-PKG downstream substrates and related kinases using this approach and selected the RAF1 protein, which may act as both a substrate and a kinase, for further validation. This showed that the RAS/RAF1/MAPK/ERK pathway may be involved in retinal degeneration in a yet unclarified mechanism, thus deserving further investigation in the future.</p>}},
  author       = {{Zhou, Jiaming and Welinder, Charlotte and Ekström, Per}},
  issn         = {{1661-6596}},
  keywords     = {{mass spectrometry; organotypic retinal explant culture; phosphoproteome; retinal degeneration}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{The Phosphoproteome of the Rd1 Mouse Retina, a Model of Inherited Photoreceptor Degeneration, Changes after Protein Kinase G Inhibition}},
  url          = {{http://dx.doi.org/10.3390/ijms24129836}},
  doi          = {{10.3390/ijms24129836}},
  volume       = {{24}},
  year         = {{2023}},
}