{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T21:09:49Z","timestamp":1779224989698,"version":"3.51.4"},"reference-count":59,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1844"],"award-info":[{"award-number":["1844"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004240","name":"Akademie V\u011bd \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:p>\n                    Acid\u2010\u03b2\u2010glucosidase (GCase,\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/iubmb.qmul.ac.uk\/enzyme\/EC3\/2\/1\/45.html\">EC3.2.1.45<\/jats:ext-link>\n                    ), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the\n                    <jats:italic>GBA1<\/jats:italic>\n                    gene. Biallelic mutations in\n                    <jats:italic>GBA1<\/jats:italic>\n                    cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme\n                    <jats:sup>\u00ae<\/jats:sup>\n                    ) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients. As a first step toward developing an alternative to the recombinant human enzymes used to treat GD, we applied the PROSS stability\u2010design algorithm to generate GCase variants with enhanced stability. One of the designs, containing 55 mutations compared to wild\u2010type human GCase, exhibits improved secretion and thermal stability. Furthermore, the design has higher enzymatic activity than the clinically used human enzyme when incorporated into an AAV vector, resulting in a larger decrease in the accumulation of lipid substrates in cultured cells. Based on stability\u2010design calculations, we also developed a machine learning\u2010based approach to distinguish benign from deleterious (i.e., disease\u2010causing)\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutations. This approach gave remarkably accurate predictions of the enzymatic activity of single\u2010nucleotide polymorphisms in the\n                    <jats:italic>GBA1<\/jats:italic>\n                    gene that are not currently associated with GD or PD. This latter approach could be applied to other diseases to determine risk factors in patients carrying rare mutations.\n                  <\/jats:p>","DOI":"10.1111\/febs.16758","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T06:38:57Z","timestamp":1676961537000},"page":"3383-3399","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Design of a stable human acid\u2010\u03b2\u2010glucosidase: towards improved Gaucher disease therapy and mutation classification"],"prefix":"10.1111","volume":"290","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7046-9440","authenticated-orcid":false,"given":"Sarka","family":"Pokorna","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"},{"name":"J.Heyrovsky Institute of Physical Chemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Khersonsky","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosalie","family":"Lipsh\u2010Sokolik","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adi","family":"Goldenzweig","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebekka","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yacov","family":"Ashani","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoav","family":"Peleg","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Core Facilities Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamar","family":"Unger","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Core Facilities Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shira","family":"Albeck","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Core Facilities Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orly","family":"Dym","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Core Facilities Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asa","family":"Tirosh","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Core Facilities Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rana","family":"Tarayra","sequence":"additional","affiliation":[{"name":"Department of Chemical and Structural Biology Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u00ebl","family":"Hocquemiller","sequence":"additional","affiliation":[{"name":"Lysogene  Neuilly\u2010sur\u2010Seine France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph","family":"Laufer","sequence":"additional","affiliation":[{"name":"Lysogene  Neuilly\u2010sur\u2010Seine France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9604-1939","authenticated-orcid":false,"given":"Shifra","family":"Ben\u2010Dor","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Core Facilities Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Israel","family":"Silman","sequence":"additional","affiliation":[{"name":"Department of Brain Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0306-3878","authenticated-orcid":false,"given":"Joel L.","family":"Sussman","sequence":"additional","affiliation":[{"name":"Department of Chemical and Structural Biology Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3177-7560","authenticated-orcid":false,"given":"Sarel J.","family":"Fleishman","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0013-0115","authenticated-orcid":false,"given":"Anthony H.","family":"Futerman","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences Weizmann Institute of Science  Rehovot Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1423"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.3.249"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420005509"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/10409239009090616"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61522-6"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21491"},{"key":"e_1_2_10_8_1","first-page":"46","article-title":"The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity?","volume":"124","author":"Shayman JA","year":"2013","journal-title":"Trans Am Clin Climatol Assoc"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.03.004"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.11.015"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2016.087"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz317"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82412-7"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2015.09.002"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.06.012"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-062917-012102"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616903114"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-89785-1"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.166964"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00239-015-9717-5"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2020.0141"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2014.00148"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.49138"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0901281"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28232"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi9002265"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01488-1"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.embor873"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V79.7.1662.bloodjournal7971662"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043310"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3265"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi240"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20676"},{"key":"e_1_2_10_36_1","first-page":"921","article-title":"Prevalence of nine mutations among Jewish and non\u2010Jewish Gaucher disease patients","volume":"53","author":"Horowitz M","year":"1993","journal-title":"Am J Hum Genet"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1086\/302925"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.150433"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)67845-2"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511110200"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24063"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-007-0135-4"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2017.11.007"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/43.8.1325"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.07.085"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-013-9455-6"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.028019"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa1071"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14945"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2014.02.029"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444906029799"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3030377"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-7652.2007.00263.x"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2647"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3026"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2008.155"},{"key":"e_1_2_10_58_1","article-title":"Differentiation of the SH\u2010SY5Y human neuroblastoma cell line","author":"Shipley MM","year":"2016","journal-title":"J Vis Exp"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101517"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380030105"}],"container-title":["The FEBS Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.16758","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/febs.16758","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.16758","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T21:28:55Z","timestamp":1692307735000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1111\/febs.16758"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":59,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1111\/febs.16758"],"URL":"https:\/\/doi.org\/10.1111\/febs.16758","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/FEBS.16758\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.16758\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.16758\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.16758\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.16758\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.16758\/v2\/decision1","asserted-by":"object"}]},"ISSN":["1742-464X","1742-4658"],"issn-type":[{"value":"1742-464X","type":"print"},{"value":"1742-4658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,23]]},"assertion":[{"value":"2022-09-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}