{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:13:38Z","timestamp":1791915218771,"version":"4.3.4"},"reference-count":64,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic kidney disease (CKD) is an established risk factor for Parkinson\u2019s disease (PD), but the molecular mechanisms linking these two conditions remain elusive. We performed a systems biology analysis by retrieving high-confidence gene\u2013disease associations from DisGeNET v7.0 (PD: score \u2265 0.8, EI \u2265 0.4; CKD: score \u2265 0.6, EI \u2265 0.4) and constructing a protein\u2013protein interaction (PPI) network via STRING v11.5 (confidence \u2265 0.700). Direct \u201cmolecular bridges\u201d between CKD and PD proteins were identified and validated using independent databases. To corroborate biological feasibility, candidate proteins were cross-referenced with ExoCarta and Vesiclepedia databases for exosomal localization. Functional enrichment, tissue expression, and pathway analyses were conducted. Despite zero gene overlap (64 PD genes, 17 CKD genes), the PPI network showed significant convergence (81 nodes, 280 edges, PPI enrichment p &lt; 1.0 \u00d7 10\u221216). Fifteen high-confidence molecular bridges were identified, including the Apolipoprotein A1 (APOA1)\u2013\u03b1-synuclein (SNCA) interaction (combined score 0.883), which was independently validated by IntAct. Functional enrichment revealed specific association of APOA1\u2013SNCA with \u201camyloid fiber formation\u201d (false discovery rate (FDR) = 0.038). Both APOA1 and SNCA are annotated as exosome components (Kyoto Encyclopedia of Genes and Genomes (KEGG) ko04147) and were confirmed as consistent cargo in plasma, urine, and platelet-derived extracellular vesicles within proteomic databases (ExoCarta IDs: 335, 6622). Global pathway analysis highlighted inflammation, oxidative stress, and the advanced glycation end product (AGE)\u2013receptor for AGE (RAGE) pathway. We propose an integrative model wherein CKD-induced dysregulation of APOA1 promotes \u03b1-synuclein misfolding and aggregation, and the co-packaging of these proteins into exosomes provides a plausible vehicle for kidney-to-brain propagation. This framework offers testable hypotheses and potential therapeutic targets for PD-CKD comorbidity.<\/jats:p>","DOI":"10.3390\/ijms27104176","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T19:10:52Z","timestamp":1778267452000},"page":"4176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The APOA1-SNCA Axis as a Molecular Bridge Between CKD and Parkinson\u2019s Disease: A Systems Biology Model of Kidney-to-Brain Propagation via Exosomal Pathways"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6079-8224","authenticated-orcid":false,"given":"Deryanaz","family":"Billur","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093 Istanbul, T\u00fcrkiye"},{"name":"Department of Molecular Medicine, Institute of Graduate Studies in Health Sciences, Istanbul University, 34126 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4624-4428","authenticated-orcid":false,"given":"Hasmet Ayhan","family":"Hanagas\u0131","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Istanbul University, 34093 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6032-0856","authenticated-orcid":false,"given":"Basar","family":"Bilgic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Istanbul University, 34093 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2641-5613","authenticated-orcid":false,"given":"Ozlem","family":"Timirci-Kahraman","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. 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