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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 (XBP1) 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 OSBPL3, C16orf74, and SLC6A1 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\u2013cell communication that have previously been linked to PD. These findings highlight a potential regulatory role of IRE in PD.<\/jats:p>","DOI":"10.3390\/ijms26146711","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:45:52Z","timestamp":1752572752000},"page":"6711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multiomics Integration of Parkinson\u2019s Disease Datasets Reveals Unexpected Roles of IRE1 in Its Pathology"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9511-4184","authenticated-orcid":false,"given":"Bianka Alexandra","family":"Pasat","sequence":"first","affiliation":[{"name":"Apoptosis Research Centre, University of Galway, H91W2TY Galway, Ireland"},{"name":"School of Biological and Chemical Sciences, University of Galway, H91W2TY Galway, Ireland"},{"name":"Research Ireland Centre for Research Training in Genomics Data Science, University of Galway, H91W2TY Galway, Ireland"},{"name":"Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8813-8754","authenticated-orcid":false,"given":"Matthieu","family":"Moncan","sequence":"additional","affiliation":[{"name":"Apoptosis Research Centre, University of Galway, H91W2TY Galway, Ireland"},{"name":"School of Biological and Chemical Sciences, University of Galway, H91W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5253-5256","authenticated-orcid":false,"given":"Eleftherios","family":"Pilalis","sequence":"additional","affiliation":[{"name":"Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str, 11527 Athens, Greece"},{"name":"e-NIOS Applications PC, 196 Al Syggrou Ave., 17671 Kallithea, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8610-8375","authenticated-orcid":false,"given":"Afshin","family":"Samali","sequence":"additional","affiliation":[{"name":"Apoptosis Research Centre, University of Galway, H91W2TY Galway, Ireland"},{"name":"C\u00daRAM Research Centre for Medical Devices, University of Galway, H91W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2078-0844","authenticated-orcid":false,"given":"Aristotelis","family":"Chatziioannou","sequence":"additional","affiliation":[{"name":"Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str, 11527 Athens, Greece"},{"name":"e-NIOS Applications PC, 196 Al Syggrou Ave., 17671 Kallithea, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-0058","authenticated-orcid":false,"given":"Adrienne M.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Apoptosis Research Centre, University of Galway, H91W2TY Galway, Ireland"},{"name":"School of Biological and Chemical Sciences, University of Galway, H91W2TY Galway, Ireland"},{"name":"C\u00daRAM Research Centre for Medical Devices, University of Galway, H91W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.4314\/bajopas.v11i1.39S","article-title":"Pathophysiology and management of parkinson disease: A review","volume":"11","author":"Samaila","year":"2019","journal-title":"Bayero J. 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