{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:51:04Z","timestamp":1790725864021,"version":"4.1.0"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6743","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Science"],"published-print":{"date-parts":[[2025,4,11]]},"abstract":"<jats:p>\n                    Variants in\n                    <jats:italic>GBA1<\/jats:italic>\n                    resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson\u2019s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of\n                    <jats:italic>GBA1<\/jats:italic>\n                    variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain\u2013containing 3 (COMMD3) protein, a component of the COMMD\/coiled-coil domain\u2013containing protein 22 (CCDC22)\/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk. Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.\n                  <\/jats:p>","DOI":"10.1126\/science.adq6650","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T14:00:01Z","timestamp":1744293601000},"page":"204-211","update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Commander complex regulates lysosomal function and is implicated in Parkinson\u2019s disease risk"],"prefix":"10.1126","volume":"388","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1090-4241","authenticated-orcid":true,"given":"Georgia","family":"Minakaki","sequence":"first","affiliation":[{"name":"Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4866-4837","authenticated-orcid":true,"given":"Nathaniel","family":"Safren","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2679-9503","authenticated-orcid":true,"given":"Bernabe I.","family":"Bustos","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7103-6671","authenticated-orcid":true,"given":"Steven J.","family":"Lubbe","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3383-9665","authenticated-orcid":true,"given":"Niccol\u00f2 E.","family":"Mencacci","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-1886","authenticated-orcid":true,"given":"Dimitri","family":"Krainc","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00785-3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0901281"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182735e9a"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.313"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2010.10.006"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam9080"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.001"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001315"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318245f476"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28200"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz350"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616332114"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25629"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx285"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28987"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.018"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.19760"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501928200"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2017.04.006"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14877"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10961"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3610"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e14-06-1073"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.04.003"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.51"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.05.029"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12221-6"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac047"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)80760-Z"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz229"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan6298"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adh3347"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-019-0872-6"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.015"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212382"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0100-17.2017"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00472-1"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1928"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E23-06-0251"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6977"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-023-01184-4"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-024-01246-1"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804766200"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.35898"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.312004"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.045963"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.06.056"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201505108"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.01.027"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx364"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1719-5"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33500-9"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adj7308"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021109108"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.410"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02309-z"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad214"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"e_1_3_2_60_2","unstructured":"B. I. Bustos bibb\/Burden-analysis-of-rare-predicted-loss-of-function-variants-in-COMMD-related-genes-for-PD: v1.0 Zenodo (2025); https:\/\/doi.org\/10.5281\/zenodo.14798968."},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25879"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202304042"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10648"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0297-x"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.3572"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.014"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1395992"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28549"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw079"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v036.i03"}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.adq6650","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T14:00:51Z","timestamp":1744293651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.adq6650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":72,"journal-issue":{"issue":"6743","published-print":{"date-parts":[[2025,4,11]]}},"alternative-id":["10.1126\/science.adq6650"],"URL":"https:\/\/doi.org\/10.1126\/science.adq6650","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,11]]},"assertion":[{"value":"2024-05-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-02","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}