{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:08:04Z","timestamp":1790644084964,"version":"4.1.0"},"reference-count":188,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Westminster"},{"name":"UCL School of Pharmacy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The detection of early molecular mechanisms and potential biomarkers in Parkinson\u2019s disease (PD) remains a challenge. Recent research has pointed to novel roles for post-translational citrullination\/deimination caused by peptidylarginine deiminases (PADs), a family of calcium-activated enzymes, in the early stages of the disease. The current study assessed brain-region-specific citrullinated protein targets and their associated protein\u2013protein interaction networks alongside PAD isozymes in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Six brain regions (cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb) were compared between controls\/shams and the pre-motor PD model. For all brain regions, there was a significant difference in citrullinated protein IDs between the PD model and the controls. Citrullinated protein hits were most abundant in cortex and hippocampus, followed by cerebellum, midbrain, olfactory bulb and striatum. Citrullinome-associated pathway enrichment analysis showed correspondingly considerable differences between the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in PD brains only were associated with neurological, metabolic, immune and hormonal functions and included the following: \u201cAxon guidance\u201d; \u201cSpinocerebellar ataxia\u201d; \u201cHippo signalling pathway\u201d; \u201cNOD-like receptor signalling pathway\u201d; \u201cPhosphatidylinositol signalling system\u201d; \u201cRap1 signalling pathway\u201d; \u201cPlatelet activation\u201d; \u201cYersinia infection\u201d; \u201cFc gamma R-mediated phagocytosis\u201d; \u201cHuman cytomegalovirus infection\u201d; \u201cInositol phosphate metabolism\u201d; \u201cThyroid hormone signalling pathway\u201d; \u201cProgesterone-mediated oocyte maturation\u201d; \u201cOocyte meiosis\u201d; and \u201cCholine metabolism in cancer\u201d. Some brain-region-specific differences were furthermore observed for the five PAD isozymes (PADs 1, 2, 3, 4 and 6), with most changes in PAD 2, 3 and 4 when comparing control and PD brain regions. Our findings indicate that PAD-mediated protein citrullination plays roles in metabolic, immune, cell signalling and neurodegenerative disease-related pathways across brain regions in early pre-motor stages of PD, highlighting PADs as targets for future therapeutic avenues.<\/jats:p>","DOI":"10.3390\/ijms252011168","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T08:56:32Z","timestamp":1729155392000},"page":"11168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Brain-Region-Specific Differences in Protein Citrullination\/Deimination in a Pre-Motor Parkinson\u2019s Disease Rat Model"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-2560","authenticated-orcid":false,"given":"Audrey","family":"Mercer","sequence":"first","affiliation":[{"name":"Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sancandi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Maclatchy","sequence":"additional","affiliation":[{"name":"Pathobiology and Extracellular Vesicles Research Group, School of Life Sciences, University of Westminster, London W1W 6XH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-3102","authenticated-orcid":false,"given":"Sigrun","family":"Lange","sequence":"additional","affiliation":[{"name":"Pathobiology and Extracellular Vesicles Research Group, School of Life Sciences, University of Westminster, London W1W 6XH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/mds.24954","article-title":"Premotor Parkinson\u2019s disease: Concepts and definitions","volume":"27","author":"Siderowf","year":"2012","journal-title":"Mov. 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