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

ABSTRACT: Inherited retinal degenerations (IRDs) are a leading cause of blindness among the young population 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 common key pathophysiological pathways in IRDs that could be used as targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated retinal proteome of three distinct IRD mouse models, comparing to sex- and age-matched wild-type mice. Specifically, we used the Pde6βRd10 (rd10) and RhoP23H/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 multi-methodological approach signifies the reliability and reproducibility of the results. The largescale retinal proteome profiling, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Retinal Cell, Retina

DISEASE(S): Retinal Degeneration

SUBMITTER: Ahmed Montaser

LAB HEAD: Zhibin Ning

PROVIDER: PXD052555 | Pride | 2024-10-10

REPOSITORIES: Pride

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			Action	DRS
	001_uOttawa_DDA_rd10_CLR_cohort_1_WT_M_A1.index	Other
	001_uOttawa_DDA_rd10_CLR_cohort_1_WT_M_A1.raw	Raw
	002_uOttawa_DDA_rd10_CLR_cohort_1_WT_M_A2.index	Other
	002_uOttawa_DDA_rd10_CLR_cohort_1_WT_M_A2.raw	Raw
	003_uOttawa_DDA_rd10_CLR_cohort_1_WT_M_A3.index	Other

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Project description:Retinal degeneration is the leading cause of irreversible blindness. Retinitis pigmentosa (RP) is a genetically heterogenous group of diseases. In the United States, approximately one in 4000 individuals is affected. RP begins with the loss of night vision due to the loss of rod photoreceptor cells. The disease progresses slowly with the loss of peripheral vision, and eventually leads to complete debilitating and irreversible blindness. The first mutation associated with human RP was identified in the gene encoding rhodopsin, the G-protein coupled receptor of rod photoreceptor cells. Mutations within the rhodopsin gene account for significant portion of RP cases. Specifically, mutations of the proline at residue 347 in rhodopsin have been linked to human RP. We are fortunate to have access to the P347S rhodopsin mutant mice. These mice represent an excellent transgenic mouse model of retinal degeneration. The P347S rhodopsin mutation is one of the best studied mutations, yet the mechanism by which the mutation causes degeneration is still unknown. One study has demonstrated that galectin-1 plays a role in degeneration of neuronal processes (1) and another study has shown that expression level of galectin-3 is elevated in retinas of patients with age-related macular degeneration. These studies in conjunction with the availibility of the P347S mutant mice have provided impetus to examine the pathogenesis of retinal degeneration in the context of the possible role of glycans and glycan-binding proteins. The time course of photoreceptor degeneration in the P347S mouse model has been carefully studied. In these mice, degeneration is barely detectable at 1 month of age, yet biochemical evidence suggests that the rod photoreceptor cells have already begun to die. At 4 months of age, approximately half of the rod photoreceptor cells have degenerated. To distinguish involvement of glycogens at the various stages of retinal degeneration, we have collected retinas of wild type and the mutant mice at four time points (1, 2, 3, and 4 months of age). This will allow us to identify the genes that target early, mid- and late stages of the retinal degeneration process. Thus we request the analysis of total 24 samples as specified below: Age Group (months) Mice No of samples at each time point 1 Wild type 3 2 Wild type 3 3 Wild type 3 4 Wild type 3 1 P347S 3 2 P347S 3 3 P347S 3 4 P347S 3 Total 24.

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

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