School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Center for Translational Vision Research, Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, California, USA; Department of Physiology and Biophysics, University of California, Irvine, California, USA.
Mol Cell Proteomics. 2024 Nov;23(11):100855. doi: 10.1016/j.mcpro.2024.100855. Epub 2024 Oct 9.
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) and Rho (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 is curated and made publicly available, facilitating the discovery of universal therapeutic targets for RP.
遗传性视网膜退行性疾病（IRDs）是发达国家年轻人致盲的主要原因。大约一半的 IRDs 最初表现为夜视力和视野逐渐丧失，这是典型的色素性视网膜炎（RP）的特征。由于基因测试的挑战，以及 RP 潜在突变的高度异质性，针对目标的基因疗法在可预见的未来不太可能成为大规模的解决方案。因此，确定 IRDs 中可能成为无突变和疾病修饰治疗（DMT）靶点的关键病理生理途径是有必要的。在这项研究中，我们研究了三种不同的 IRD 小鼠模型的视网膜蛋白质组，与性别和年龄匹配的野生型小鼠进行了比较。具体来说，我们分别使用 Pde6β（rd10）和 Rho（P23H）小鼠模型作为常染色体隐性和常染色体显性 RP 的模型，以及 Rpe65 小鼠模型作为 Leber 先天性黑矇 2 型（LCA2）的模型。这些小鼠被安置在两个不同的机构中，并使用 LC-MS 在三个不同的设施/仪器中进行分析，采用数据依赖和数据独立的采集模式。这种跨机构和多方法的方法证明了结果的可靠性和可重复性。视网膜蛋白质组的大规模分析，加上体内视网膜电图记录，为我们比较疾病表型和严重程度提供了可靠的基础。尽管在所有三种模型中都观察到明显的炎症、细胞应激和光转导下调，但 RP 和 LCA2 的潜在病理学存在许多差异，仅共享四个一般的 KEGG 途径。相反，在两种 RP 模型中，尽管 rd10 和 P23H 小鼠中 rod 细胞死亡的机制不同，但我们发现蛋白质组表型惊人地趋同。我们的数据突出了 cAMP 和 cGMP 第二信使信号通路作为治疗干预的潜在靶点。蛋白质组学数据被整理并公开提供，促进了 RP 通用治疗靶点的发现。
