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

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 a 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 large-scale
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 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
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 are curated and made publicly
available, facilitating the discovery of universal therapeutic targets for
RP.