Retinal proteome profiling of inherited retinal degeneration across three different mouse models suggests common drug targets in retinitis pigmentosa

Tools

Montaser, Ahmed B., Gao, Fangyuan, Peters, Danielle, Vainionpää, Katri, Zhibin, Ning, Skowronska-Krawczyk, Dorota, Figeys, Daniel, Palczewski, Krzysztof and Leinonen, Henri (2024) Retinal proteome profiling of inherited retinal degeneration across three different mouse models suggests common drug targets in retinitis pigmentosa. Molecular & Cellular Proteomics, 23 (11). ISSN 1535-9484

[thumbnail of Retinal proteome profiling of inherited retinal degeneration across three different mouse models suggests common drug targets in retinitis pigmentosa]
Preview
 PDF (Retinal proteome profiling of inherited retinal degeneration across three different mouse models suggests common drug targets in retinitis pigmentosa) - Published Version
Available under License Creative Commons Attribution.
Download (2MB) | Preview

Abstract

Inherited retinal degenerations (IRDs) are a leading cause of blindness among the population of young people in the developed world. Approximately half of IRDs initially manifest as gradual loss of night vision and visual fields, characteristic of retinitis pigmentosa (RP). Due to challenges in genetic testing, and the large heterogeneity of mutations underlying RP, targeted gene therapies are an impractical largescale solution in the foreseeable future. For this reason, identifying key pathophysiological pathways in IRDs that could be targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated the retinal proteome of three distinct IRD mouse models, in comparison to sex- and age-matched wild-type mice. Specifically, we used the Pde6β Rd10 (rd10) and Rho P23H/WT (P23H) mouse models of autosomal recessive and autosomal dominant RP, respectively, as well as the Rpe65 −/− mouse model of Leber’s congenital amaurosis type 2 (LCA2). The mice were housed at two distinct institutions and analyzed using LC-MS in three separate facilities/instruments following data-dependent and data-independent acquisition modes. This cross-institutional and multimethodological approach signifies the reliability and reproducibility of the results. The large-scale profiling of the retinal proteome, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity. Despite evident inflammation, cellular stress, and downscaled phototransduction observed consistently across all three models, the underlying pathologies of RP and LCA2 displayed many differences, sharing only four general KEGG pathways. The opposite is true for the two RP models in which we identify remarkable convergence in proteomic phenotype even though the mechanism of primary rod death in rd10 and P23H mice is different. Our data highlights the cAMP and cGMP second-messenger signaling pathways as potential targets for therapeutic intervention. The proteomic data is curated and made publicly available, facilitating the discovery of universal therapeutic targets for RP.

Item Type: Article
Additional Information: Data Availability: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (92) via the PRIDE partner repository (93) with the dataset identifier PXD052547 (UCI_DDA_P23H_cohort 1), PXD052549 (UCI_DDA_rd10_DR_cohort 2), PXD052554 (UCI_DDA_Rpe65−/− cohort 1), PXD052555 (UCI_DDA_rd10_CLR_cohort 1) or via skyline and Panorama public repository (94) with the dataset identifiers PXD052698 (UEF_DIA_rd10_DR_cohort 3) and PXD052598 (UEF_DIA_P23H_cohort 2). Examples of how to access fully annotated spectra of the deposited data are illustrated in supp1emental Figs. S11–S14. Funding and additional information: H. L. was supported by grants from the Research Council of Finland (grant 346295), Business Finland, Emil Aaltonen Foundation, Sigrid Jusélius Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Eye and Tissue Bank Foundation, Retina Registered Association (Finland), and Sokeain Ystävät/De Blindas Vänner Registered Association. This research was supported, in part, by grants from the National Eye Institute (NEI): EY034501 and EY009339 (K. P.), and The Canadian Institute for Advanced Research (D. F. and K. P). The authors acknowledge support to the Gavin Herbert Eye Institute at the University of California, Irvine from an unrestricted grant from Research to Prevent Blindness and from NIH core grant P30 EY034070.
Uncontrolled Keywords: -) inherited retinal degenerations rd10 retinal degeneration retinal proteome retinitis pigmentosa,analytical chemistry,molecular biology,biochemistry ,/dk/atira/pure/subjectarea/asjc/1600/1602
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 02 Sep 2025 16:30
Last Modified: 10 Nov 2025 16:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/100275
DOI: 10.1016/j.mcpro.2024.100855

Downloads

Downloads per month over past year

Actions (login required)

View Item View Item