{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:55:58Z","timestamp":1787021758808,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010847","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T00:00:00Z","timestamp":1675036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006637","name":"UCL School of Pharmacy","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006637","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["18063"],"award-info":[{"award-number":["18063"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/M508123\/1"],"award-info":[{"award-number":["EP\/M508123\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["UKDRI-3003"],"award-info":[{"award-number":["UKDRI-3003"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T04604X\/1"],"award-info":[{"award-number":["MR\/T04604X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Health Research University College London Hospitals Biomedical Research Centre"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Mutations in\n                    <jats:italic>LRRK2<\/jats:italic>\n                    are the most common genetic cause of Parkinson\u2019s disease. Despite substantial research efforts, the physiological and pathological role of this multidomain protein remains poorly defined. In this study, we used a systematic approach to construct the general protein-protein interactome around LRRK2, which was then evaluated taking into consideration the differential expression patterns and the co-expression behaviours of the LRRK2 interactors in 15 different healthy tissue types. The LRRK2 interactors exhibited distinct expression features in the brain as compared to the peripheral tissues analysed. Moreover, a high degree of similarity was found for the LRRK2 interactors in\n                    <jats:italic>putamen<\/jats:italic>\n                    ,\n                    <jats:italic>caudate<\/jats:italic>\n                    and\n                    <jats:italic>nucleus accumbens<\/jats:italic>\n                    , thus defining a potential LRRK2 functional cluster within the\n                    <jats:italic>striatum<\/jats:italic>\n                    . The general LRRK2 interactome paired with the expression profiles of its members constitutes a powerful tool to generate tissue-specific LRRK2 interactomes. We exemplified the generation of the tissue-specific LRRK2 interactomes and explored the functions highlighted by the \u201ccore LRRK2 interactors\u201d in the\n                    <jats:italic>striatum<\/jats:italic>\n                    in comparison with the\n                    <jats:italic>cerebellum<\/jats:italic>\n                    . Finally, we illustrated how the LRRK2 general interactome reported in this manuscript paired with the expression profiles can be used to trace the relationship between LRRK2 and specific interactors of interest, here focusing on the LRRK2 interactors belonging to the Rab protein family.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010847","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T14:55:51Z","timestamp":1675090551000},"page":"e1010847","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4520-8476","authenticated-orcid":true,"given":"Yibo","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikoleta","family":"Vavouraki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth C.","family":"Lovering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Escott-Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick A.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Manzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"pcbi.1010847.ref001","doi-asserted-by":"crossref","first-page":"E4357","DOI":"10.1073\/pnas.1523708113","article-title":"Structural model of the dimeric Parkinson\u2019s protein LRRK2 reveals a compact architecture involving distant interdomain contacts","volume":"113","author":"G Guaitoli","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1010847.ref002","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3109\/01677063.2011.627072","article-title":"Leucine-rich repeat kinase 2 (LRRK2) cellular biology: A review of recent advances in identifying physiological substrates and cellular functions.","author":"RE Drolet","year":"2011","journal-title":"Journal of Neurogenetics"},{"key":"pcbi.1010847.ref003","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S1474-4422(08)70117-0","article-title":"Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson\u2019s disease: a case-control study","volume":"7","author":"DG Healy","year":"2008","journal-title":"Lancet Neurol"},{"key":"pcbi.1010847.ref004","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41582-019-0301-2","article-title":"LRRK2 in Parkinson disease: challenges of clinical trials","author":"E Tolosa","year":"2020","journal-title":"Nature Reviews Neurology."},{"key":"pcbi.1010847.ref005","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2147\/TACG.S33966","article-title":"Genetic variants associated with Crohn\u2019s disease","author":"S Michail","year":"2013","journal-title":"Application of Clinical Genetics."},{"key":"pcbi.1010847.ref006","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1002\/ibd.21651","article-title":"Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn\u2019s disease and ulcerative colitis.","volume":"17","author":"J Umeno","year":"2011","journal-title":"Inflamm Bowel Dis"},{"key":"pcbi.1010847.ref007","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ng.717","article-title":"Genome-wide meta-analysis increases to 71 the number of confirmed Crohn\u2019s disease susceptibility loci","volume":"42","author":"A Franke","year":"2010","journal-title":"Nat Genet"},{"key":"pcbi.1010847.ref008","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/35079107","article-title":"Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn\u2019s disease","volume":"411","author":"JP Hugot","year":"2001","journal-title":"Nature"},{"key":"pcbi.1010847.ref009","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/ng.175","article-title":"Genome-wide association defines more than 30 distinct susceptibility loci for Crohn\u2019s disease","volume":"40","author":"JC Barrett","year":"2008","journal-title":"Nat Genet"},{"key":"pcbi.1010847.ref010","article-title":"Functional variants in the LRRK2 gene confer shared effects on risk for Crohn\u2019s disease and Parkinson\u2019s disease.","volume":"10","author":"KY Hui","year":"2018","journal-title":"Sci Transl Med"},{"key":"pcbi.1010847.ref011","article-title":"A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy.","volume":"10","author":"VM Fava","year":"2016","journal-title":"PLoS Negl Trop Dis."},{"key":"pcbi.1010847.ref012","first-page":"699066","article-title":"LRRK2 regulates innate immune responses and neuroinflammation during Mycobacterium tuberculosis infection","author":"CG Weindel","year":"2019","journal-title":"bioRxiv"},{"key":"pcbi.1010847.ref013","first-page":"1","article-title":"LRRK2 Biology from structure to dysfunction: Research progresses, but the themes remain the same.","author":"DC Berwick","year":"2019","journal-title":"Molecular Neurodegeneration."},{"key":"pcbi.1010847.ref014","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1001\/jamaneurol.2014.1973","article-title":"Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease a pooled analysis","volume":"72","author":"I Agalliu","year":"2015","journal-title":"JAMA Neurol"},{"key":"pcbi.1010847.ref015","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1002\/mds.23314","article-title":"LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease","volume":"25","author":"R Saunders-Pullman","year":"2010","journal-title":"Mov Disord"},{"key":"pcbi.1010847.ref016","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/1479-7364-3-3-291","article-title":"Protein-protein interaction databases: keeping up with growing interactomes","volume":"3","author":"B Lehne","year":"2009","journal-title":"Hum Genomics"},{"key":"pcbi.1010847.ref017","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nbt825","article-title":"Global protein function prediction from protein-protein interaction networks","volume":"21","author":"A Vazquez","year":"2003","journal-title":"Nat Biotechnol"},{"key":"pcbi.1010847.ref018","article-title":"Computational analysis of the LRRK2 interactome.","volume":"2015","author":"C Manzoni","year":"2015","journal-title":"PeerJ"},{"key":"pcbi.1010847.ref019","first-page":"1390","article-title":"A visual review of the interactome of LRRK2: Using deep-curated molecular interaction data to represent biology","author":"P Porras","year":"2015","journal-title":"Proteomics. Wiley-VCH Verlag"},{"key":"pcbi.1010847.ref020","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1002\/cne.23583","article-title":"Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents","volume":"522","author":"AB West","year":"2014","journal-title":"J Comp Neurol"},{"key":"pcbi.1010847.ref021","article-title":"Comparison of gene expression profiles in the blood, hippocampus and prefrontal cortex of rats.","volume":"1","author":"SH Witt","year":"2013","journal-title":"silico Pharmacol."},{"key":"pcbi.1010847.ref022","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3233\/JPD-130174","article-title":"Measurement of LRRK2 and Ser910\/935 Phosphorylated LRRK2 in Peripheral Blood Mononuclear Cells from Idiopathic Parkinson\u2019s Disease Patients.","volume":"3","author":"N Dzamko","year":"2013","journal-title":"J Parkinsons Dis"},{"key":"pcbi.1010847.ref023","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jneuroim.2010.07.021","article-title":"LRRK2 is expressed in B-2 but not in B-1 B cells, and downregulated by cellular activation","volume":"229","author":"M Kubo","year":"2010","journal-title":"J Neuroimmunol"},{"key":"pcbi.1010847.ref024","doi-asserted-by":"crossref","first-page":"e21519","DOI":"10.1371\/journal.pone.0021519","article-title":"Regulation of LRRK2 Expression Points to a Functional Role in Human Monocyte Maturation.","volume":"6","author":"J Th\u00e9venet","year":"2011","journal-title":"PLoS One."},{"key":"pcbi.1010847.ref025","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/j.1471-4159.2006.03919.x","article-title":"Distribution of PINK1 and LRRK2 in rat and mouse brain","volume":"98","author":"JM Taymans","year":"2006","journal-title":"J Neurochem"},{"key":"pcbi.1010847.ref026","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1042\/BCJ20170803","article-title":"Interrogating Parkinson\u2019s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils","volume":"475","author":"Y Fan","year":"2018","journal-title":"Biochem J"},{"key":"pcbi.1010847.ref027","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/humu.20668","article-title":"Comprehensive analysis of LRRK2 in publicly available Parkinson\u2019s disease cases and neurologically normal controls","volume":"29","author":"C Pais\u00e1n-Ru\u00edz","year":"2008","journal-title":"Hum Mutat"},{"key":"pcbi.1010847.ref028","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-018-0240-1","article-title":"Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration.","volume":"13","author":"GR Jeong","year":"2018","journal-title":"Mol Neurodegener"},{"key":"pcbi.1010847.ref029","first-page":"165632","article-title":"The LRRK2-RAB axis in regulation of vesicle trafficking and \u03b1-synuclein propagation.","author":"EJ Bae","year":"2020"},{"key":"pcbi.1010847.ref030","first-page":"707273","article-title":"Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions.","author":"J Obergasteiger","year":"2019","journal-title":"bioRxiv"},{"key":"pcbi.1010847.ref031","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep35106","article-title":"MTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1.","volume":"6","author":"C Manzoni","year":"2016","journal-title":"Sci Rep"},{"key":"pcbi.1010847.ref032","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1016\/j.bbamcr.2013.07.020","article-title":"Inhibition of LRRK2 kinase activity stimulates macroautophagy","volume":"1833","author":"C Manzoni","year":"2013","journal-title":"Biochim Biophys Acta\u2014Mol Cell Res"},{"key":"pcbi.1010847.ref033","first-page":"1","article-title":"LRRK2 levels in immune cells are increased in Parkinson\u2019s disease.","volume":"3","author":"DA Cook","year":"2017","journal-title":"npj Park Dis."},{"key":"pcbi.1010847.ref034","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2002680","article-title":"LRRK2 and human disease: a complicated question or a question of complexes?","volume":"5","author":"PA Lewis","year":"2012","journal-title":"Sci Signal."},{"key":"pcbi.1010847.ref035","doi-asserted-by":"crossref","DOI":"10.1186\/s12964-020-00554-5","article-title":"PINOT: An intuitive resource for integrating protein-protein interactions","volume":"18","author":"JE Tomkins","year":"2020","journal-title":"Cell Commun Signal"},{"key":"pcbi.1010847.ref036","doi-asserted-by":"crossref","first-page":"D408","DOI":"10.1093\/nar\/gkw985","article-title":"HIPPIE v2.0: Enhancing meaningfulness and reliability of protein-protein interaction networks","volume":"45","author":"G Alanis-Lobato","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010847.ref037","doi-asserted-by":"crossref","first-page":"D567","DOI":"10.1093\/nar\/gkx1116","article-title":"Molecular Interaction Search Tool (MIST): An integrated resource for mining gene and protein interaction data.","volume":"46","author":"Y Hu","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010847.ref038","author":"M. Carlson","year":"2021","journal-title":"UniProt.ws: R Interface to UniProt Web Services"},{"key":"pcbi.1010847.ref039","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"G:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update).","volume":"47","author":"U Raudvere","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010847.ref040","first-page":"1","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"key":"pcbi.1010847.ref041","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2164-10-327","article-title":"Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells","volume":"10","author":"MJ Mason","year":"2009","journal-title":"BMC Genomics"},{"key":"pcbi.1010847.ref042","doi-asserted-by":"crossref","first-page":"134","DOI":"10.5607\/en.2019.28.2.134","article-title":"Rab GTPases as physiological substrates of LRRK2 kinase.","author":"W Seol","year":"2019","journal-title":"Experimental Neurobiology."},{"key":"pcbi.1010847.ref043","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1038\/ejhg.2010.125","article-title":"Genetic variability at the PARK16 locus","volume":"18","author":"A Tucci","year":"2010","journal-title":"Eur J Hum Genet"},{"key":"pcbi.1010847.ref044","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1016\/j.bbrc.2017.12.024","article-title":"Parkinson\u2019s disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology","volume":"495","author":"T Fujimoto","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"pcbi.1010847.ref045","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.neuron.2012.11.033","article-title":"RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson\u2019s disease risk","volume":"77","author":"DA MacLeod","year":"2013","journal-title":"Neuron"},{"key":"pcbi.1010847.ref046","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15252\/embj.201798099","article-title":"Rab29 activation of the Parkinson\u2019s disease-associated LRRK2 kinase","volume":"37","author":"E Purlyte","year":"2018","journal-title":"EMBO J"},{"key":"pcbi.1010847.ref047","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1042\/BST20180469","article-title":"The role of LRRK2 in cytoskeletal dynamics","author":"L Civiero","year":"2018","journal-title":"Biochemical Society Transactions"},{"key":"pcbi.1010847.ref048","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/gigascience\/giy071","article-title":"Consistent decreased activity in the putamen in Parkinson\u2019s disease: a meta-analysis and an independent validation of resting-state fMRI.","volume":"7","author":"J Wang","year":"2018","journal-title":"Gigascience"},{"key":"pcbi.1010847.ref049","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/ana.410320206","article-title":"Impaired mesial frontal and putamen activation in Parkinson\u2019s disease: A positron emission tomography study","volume":"32","author":"ED Playford","year":"1992","journal-title":"Ann Neurol"},{"key":"pcbi.1010847.ref050","doi-asserted-by":"crossref","first-page":"e01073","DOI":"10.1002\/brb3.1073","article-title":"Altered resting-state functional connectivity of the putamen and internal globus pallidus is related to speech impairment in Parkinson\u2019s disease","volume":"8","author":"JL Manes","year":"2018","journal-title":"Brain Behav"},{"key":"pcbi.1010847.ref051","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1093\/brain\/awz007","article-title":"Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control","volume":"142","author":"J Hammes","year":"2019","journal-title":"Brain"},{"key":"pcbi.1010847.ref052","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1093\/brain\/awz298","article-title":"Lower nucleus accumbens \u03b1-synuclein load and D3 receptor levels in Parkinson\u2019s disease with impulsive compulsive behaviours","volume":"142","author":"P Barbosa","year":"2019","journal-title":"Brain"},{"key":"pcbi.1010847.ref053","doi-asserted-by":"crossref","first-page":"E9115","DOI":"10.1073\/pnas.1812196115","article-title":"LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis","volume":"115","author":"T Eguchi","year":"2018","journal-title":"Proc Natl Acad Sci U S A"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010847","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010847","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T14:00:36Z","timestamp":1675951236000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010847"}},"subtitle":[],"editor":[{"given":"Miguel A.","family":"Andrade-Navarro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,30]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010847","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,30]]}}}