{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:39:10Z","timestamp":1790285950484,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023GLLH0312"],"award-info":[{"award-number":["2023GLLH0312"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The pathogenesis of Parkinson's disease (PD) is closely linked to ferroptosis, yet the mechanism by which ferroptosis\u2010related proteins modulate PD risk through genetic variations remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed two\u2010sample Mendelian randomization (MR) analyses using protein quantitative trait loci (pQTLs) from the UKB\u2010PPP and deCODE studies as instrumental variables, combined with PD genome\u2010wide association study (GWAS) data. The inverse variance weighting (IVW) method served as the primary analytical approach to identify PD\u2010associated proteins. To assess the role of ferroptosis\u2010related proteins in PD, a two\u2010step MR mediation analysis was conducted, followed by multiple sensitivity analyses. Transcriptomic datasets were analyzed to confirm the differential expression of genes encoding prioritized proteins. Publicly available single\u2010cell RNA sequencing data were utilized to investigate cell\u2010type\u2010specific expression patterns and functional pathways of key proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 210 proteins significantly associated with PD were identified (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.05). Mediation analysis demonstrated that CCNE1 mediated 44.17% of the neuroprotective effect (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      = \u22120.503,\n                      <jats:italic>p<\/jats:italic>\n                      = 5.8\u00a0\u00d7\u00a010\n                      <jats:sup>\u22124<\/jats:sup>\n                      ) through upregulating PARP16 expression (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      = 0.318,\n                      <jats:italic>p<\/jats:italic>\n                      = 2.36\u00a0\u00d7\u00a010\n                      <jats:sup>\u221218<\/jats:sup>\n                      ), with CCNE1's differential expression further validated in transcriptomic datasets. Single\u2010cell analysis demonstrated that CCNE1 and PARP16 are specifically highly expressed in neurons (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), with neurons being significantly enriched in neural survival and synaptic plasticity pathways. The cell interaction network revealed that neurons specifically communicate with astrocytes via the NRG3\u2010ERBB4 pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides the first molecular insight into how CCNE1 exerts neuroprotective effects through the regulation of the ferroptosis key protein PARP16, offering a novel perspective for PD mechanism research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.71110","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T07:00:07Z","timestamp":1764486007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CCNE1 Exerts a Protective Effect on Parkinson's Disease by Regulating Ferroptosis\u2010Related Proteins"],"prefix":"10.1002","volume":"15","author":[{"given":"Jia","family":"Fu","sequence":"first","affiliation":[{"name":"Chifeng Municipal Hospital  Chifeng City Inner Mongolia Autonomous Region China"},{"name":"The First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital  Chifeng City Inner Mongolia Autonomous Region China"},{"name":"The First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Mi","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital  Chifeng City Inner Mongolia Autonomous Region China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital  Chifeng City Inner Mongolia Autonomous Region China"},{"name":"The First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital  Chifeng City Inner Mongolia Autonomous Region China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8809-6523","authenticated-orcid":false,"given":"Lifen","family":"Yao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13205\u2010023\u201003553\u20108"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12020261"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.Cd\u201024\u20100775"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.75647"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.02267"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787\u2010025\u201001672\u20107"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14101269"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1528604"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.17219"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.919731"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1475934"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010021\u201000978\u2010w"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.00830"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.21037\/jgo\u201022\u2010341"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics10050279"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102654"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398\u2010023\u201002553\u20109"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/md.0000000000041218"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15020214"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100619\u20100"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad736"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.Cd\u201023\u20101220"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.10317"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.4103\/nrr.Nrr\u2010d\u201023\u201001265"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/7769355"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041\u2010024\u201001099\u20101"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(19)30320\u20105"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010006"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010024\u201001590\u20101"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14020385"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyac165"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3192"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n2233"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab446"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","unstructured":"Song Y. T.Ye L. R.Roberts N. B.Larson andS. J.Winham.2023. \u201cMendelian Randomization in Hepatology: A Review of Principles Opportunities and Challenges.\u201dHepatology.https:\/\/doi.org\/10.1097\/hep.0000000000000649.","DOI":"10.1097\/HEP.0000000000000649"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006592\u20106"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.07.018"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010023\u201001420\u20102"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13072\u2010022\u201000445\u20108"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010022\u201001424\u20106"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2025.01.010"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010023\u201004794\u20102"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajcnut.2023.01.005"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010024\u201004197\u20102"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202300325"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106549"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102477"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40246\u2010022\u201000388\u2010x"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1080\/00207454.2021.1924705"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252313042"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/s2666\u20107568(24)00094\u20101"}],"container-title":["Brain and Behavior"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/brb3.71110","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/brb3.71110","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/brb3.71110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:44:59Z","timestamp":1789980299000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/brb3.71110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,29]]},"references-count":51,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/brb3.71110"],"URL":"https:\/\/doi.org\/10.1002\/brb3.71110","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/BRB3.71110\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/BRB3.71110\/v1\/review1","asserted-by":"object"}]},"ISSN":["2162-3279","2162-3279"],"issn-type":[{"value":"2162-3279","type":"print"},{"value":"2162-3279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,29]]},"assertion":[{"value":"2025-04-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71110"}}