Pasat Bianka Alexandra, Moncan Matthieu, Pilalis Eleftherios, Samali Afshin, Chatziioannou Aristotelis, Gorman Adrienne M
Apoptosis Research Centre, University of Galway, H91W2TY Galway, Ireland.
School of Biological and Chemical Sciences, University of Galway, H91W2TY Galway, Ireland.
Int J Mol Sci. 2025 Jul 12;26(14):6711. doi: 10.3390/ijms26146711.
Parkinson's disease (PD) is the second most common neurodegenerative disease. It primarily affects the motor system but is also associated with a range of cognitive impairments that can manifest early in disease progression, indicating its multifaceted nature. In this paper, we performed a meta-analysis of transcriptomics and proteomics data using MultiOmicsIntegrator to gain insights into the post-transcriptional modifications and deregulated pathways associated with this disease. Our results reveal differential isoform usage between control and PD patient brain samples that result in enriched alternative splicing events, including an extended UTR length, domain loss, and the upregulation of non-coding isoforms. We found that Inositol-Requiring Enzyme 1 (IRE1) is active in PD samples and examined the role of its downstream signaling through X-box binding mRNA 1 () and regulated IRE1-dependent decay (RIDD). We identified several RIDD candidates and showed that the enriched alternative splicing events observed are associated with RIDD. Moreover, in vitro mRNA cleavage assays demonstrated that , , and mRNAs are targets of IRE1 RNAse activity. Finally, a pathway enrichment analysis of both XBP1s and RIDD targets in the PD samples uncovered associations with processes such as immune response, oxidative stress, signal transduction, and cell-cell communication that have previously been linked to PD. These findings highlight a potential regulatory role of IRE in PD.
帕金森病（PD）是第二常见的神经退行性疾病。它主要影响运动系统，但也与一系列认知障碍有关，这些认知障碍可在疾病进展早期出现，表明其具有多方面的性质。在本文中，我们使用MultiOmicsIntegrator对转录组学和蛋白质组学数据进行了荟萃分析，以深入了解与该疾病相关的转录后修饰和失调途径。我们的结果揭示了对照和PD患者脑样本之间不同的异构体使用情况，这导致了丰富的可变剪接事件，包括延长的UTR长度、结构域丢失和非编码异构体的上调。我们发现肌醇需求酶1（IRE1）在PD样本中具有活性，并通过X盒结合mRNA 1（）和调节IRE1依赖性衰变（RIDD）研究了其下游信号传导的作用。我们鉴定了几个RIDD候选物，并表明观察到的丰富的可变剪接事件与RIDD相关。此外，体外mRNA切割试验表明，、和mRNA是IRE1 RNase活性的靶标。最后，对PD样本中XBP1s和RIDD靶标的通路富集分析揭示了与免疫反应、氧化应激、信号转导和细胞间通讯等过程的关联，这些过程先前已与PD相关联。这些发现突出了IRE在PD中的潜在调节作用。
