{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T22:29:42Z","timestamp":1773181782287,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009794","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T00:00:00Z","timestamp":1632355200000}}],"reference-count":83,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T00:00:00Z","timestamp":1631491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100003390","name":"Fritz Thyssen Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003390","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["BR 1746\/6-2 and BR 1746\/3"],"award-info":[{"award-number":["BR 1746\/6-2 and BR 1746\/3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Research Council","award":["Zf-BrainReg"],"award-info":[{"award-number":["Zf-BrainReg"]}]},{"name":"Sigrid Juselius Foundation"},{"DOI":"10.13039\/501100004012","name":"Jane and Aatos Erkko Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    LRRK2 gain-of-function is considered a major cause of Parkinson\u2019s disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish\n                    <jats:italic>lrrk2<\/jats:italic>\n                    locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to\n                    <jats:italic>lrrk2<\/jats:italic>\n                    , the paralog gene\n                    <jats:italic>lrrk1<\/jats:italic>\n                    is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009794","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T13:32:31Z","timestamp":1631539951000},"page":"e1009794","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8135-7794","authenticated-orcid":true,"given":"Stefano","family":"Suzzi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reiner","family":"Ahrendt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0283-0211","authenticated-orcid":true,"given":"Stefan","family":"Hans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana A.","family":"Semenova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avinash","family":"Chekuru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1228-6846","authenticated-orcid":true,"given":"Paul","family":"Wirsching","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5610-0866","authenticated-orcid":true,"given":"Volker","family":"Kroehne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-6504","authenticated-orcid":true,"given":"Sayg\u0131n","family":"Bilican","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shady","family":"Sayed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0915-3316","authenticated-orcid":true,"given":"Sylke","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Spie\u00df","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7400-8054","authenticated-orcid":true,"given":"Anja","family":"Machate","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6207-1889","authenticated-orcid":true,"given":"Jan","family":"Kaslin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1189-5132","authenticated-orcid":true,"given":"Pertti","family":"Panula","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5711-6512","authenticated-orcid":true,"given":"Michael","family":"Brand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"issue":"16","key":"pgen.1009794.ref001","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1016\/j.yexcr.2007.07.007","article-title":"The 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Nuytemans","year":"2010","journal-title":"Hum Mutat"},{"issue":"6","key":"pgen.1009794.ref007","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/s41591-020-0893-5","article-title":"The effect of LRRK2 loss-of-function variants in humans","volume":"26","author":"N Whiffin","year":"2020","journal-title":"Nature Medicine"},{"issue":"7","key":"pgen.1009794.ref008","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1002\/humu.22075","article-title":"Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence of purifying selection and independent origin of the p.Arg1628Pro mutation in Europe","volume":"33","author":"JP Rubio","year":"2012","journal-title":"Human Mutation"},{"issue":"6","key":"pgen.1009794.ref009","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.neuron.2009.11.006","article-title":"Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson\u2019s Disease-related Mutant 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Sheng","year":"2010","journal-title":"PLoS Genet."},{"issue":"6","key":"pgen.1009794.ref036","doi-asserted-by":"crossref","first-page":"e20630","DOI":"10.1371\/journal.pone.0020630","article-title":"Disruption of LRRK2 does not cause specific loss of dopaminergic neurons in zebrafish.","volume":"6","author":"G Ren","year":"2011","journal-title":"PLoS One."},{"issue":"8","key":"pgen.1009794.ref037","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/jnr.23754","article-title":"LRRK2 knockdown in zebrafish causes developmental defects, neuronal loss, and synuclein aggregation","volume":"94","author":"S Prabhudesai","year":"2016","journal-title":"J Neurosci Res"},{"key":"pgen.1009794.ref038","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nature14580","article-title":"Genetic compensation induced by deleterious mutations but not gene knockdowns","volume":"524","author":"A 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