Abstract：
X-linked retinoschisis (XLRS) is among the most commonly inherited degenerative retinopathies. XLRS is caused by functional impairment of RS1. However, the molecular mechanisms underlying RS1 malfunction remain largely uncharacterized. Here, we performed a data-independent acquisition-mass spectrometry-based proteomic analysis in RS1-null mouse retina with different postal days (Ps), including the onset (P15) and early progression stage (P56). Gene set enrichment analysis showed that type I interferon-mediated signaling was upregulated and photoreceptor proteins responsible for detection of light stimuli were downregulated at P15. Positive regulation of Tor signaling was downregulated and nuclear transcribed mRNA catabolic process nonsense-mediated decay was upregulated at P56. Moreover, the differentially expressed proteins at P15 were enriched in metabolism of RNA and RNA destabilization. A broader subcellular localization distribution and enriched proteins in visual perception and phototransduction were evident at P56. Combined transcriptomic-proteomic analysis revealed that functional impairments, including detection of visible light, visual perception, and visual phototransduction, occurred at P21 and continued until P56. Our work provides insights into the molecular mechanisms underlying the onset and progression of an XLRS mouse model during the early stages, thus enhancing the understanding of the mechanism of XLRS.
摘要：
X连锁视网膜裂(XLRS)是最常见的遗传性退行性视网膜病变之一。XLRS是由RS1的功能损害引起的。然而,RS1故障的分子机制在很大程度上仍未表征。这里,我们在不同邮递日（Ps）的RS1-null小鼠视网膜中进行了基于数据独立采集质谱的蛋白质组学分析，包括发作期(P15)和早期进展期(P56)。基因集富集分析表明，I型干扰素介导的信号传导被上调，负责检测光刺激的光感受器蛋白在P15下调。在P56，Tor信号传导的正调节被下调，核转录的mRNA分解代谢过程无义介导的衰变被上调。此外，P15的差异表达蛋白在RNA代谢和RNA不稳定中富集。在P56处明显存在更广泛的亚细胞定位分布和在视觉感知和光转导中富集的蛋白质。联合转录-蛋白质组分析显示，功能损伤，包括可见光的检测，视觉感知，和视觉光传导，发生在P21并持续到P56。我们的工作提供了对XLRS小鼠模型早期发病和进展的分子机制的见解。从而加深对XLRS机制的理解。
