{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:28:16Z","timestamp":1782930496898,"version":"3.54.5"},"reference-count":75,"publisher":"National Academy of Sciences","issue":"27","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech, Inc.","doi-asserted-by":"crossref","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:p>\n                    Mutations in the\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson\u2019s disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic aggregation of \u03b1-Synuclein in PD. As such, boosting the lysosomal activity of GCase is a therapeutic strategy to ameliorate substrate accumulation and prevent associated neurotoxicity. To identify the regulators of GCase activity in lysosomes, we conducted a genome-wide screen in primary mouse macrophages using a fluorescent enzyme activity reporter. By validating the screen hits in cellular biochemical and profiling assays, we identified pathways that promote or inhibit lysosomal GCase activity. Our screen identified PLCG2 as a regulator of lysosomal GCase activity. Mechanistically, PLCG2 depletion accumulates Golgi-associated phosphatidylinositols, promoting the transport of mutant GCase into lysosomes while reducing its Golgi-associated pool. Functionally, PLCG2 depletion boosts the activity of lysosomal mutant GCase, the cellular flux of glucosylceramide, and the clearance of pathogenic GCase substrates. In summary, our screen has uncovered the regulators of GCase abundance and trafficking at a whole-genome scale and identified potential pathways for future therapeutic interventions in Gaucher and Parkinson\u2019s to boost the activity of this enzyme in lysosomes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2514112123","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:41:20Z","timestamp":1782927680000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7611-259X","authenticated-orcid":false,"given":"Jessica","family":"Lawrence","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineet Vinay","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2738-3311","authenticated-orcid":false,"given":"Chan Lek","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-5412","authenticated-orcid":false,"given":"Marinella","family":"Callow","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Juste","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewakar","family":"Sangaraju","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism and Pharmacology, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-4367","authenticated-orcid":false,"given":"Baris","family":"Bingol","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020441"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0901281"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00999-z"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-00416-6"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14387"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24777"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167749"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318225ab77"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106343"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-018-0860-4"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1108197108"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz005"},{"key":"e_1_3_4_13_2","first-page":"2712","article-title":"The contribution of mutant GBA to the development of Parkinson disease in Drosophila","volume":"25","author":"Maor G.","year":"2016","unstructured":"G. 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Bingol Data from \u201cLawrence et al. 2026 a genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity.\u201d Mendeley. https:\/\/doi.org\/10.17632\/zhpg8xshp9.1. 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