{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:33:03Z","timestamp":1782977583401,"version":"3.54.5"},"reference-count":68,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1300\/13"],"award-info":[{"award-number":["1300\/13"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The human GBA1 gene encodes lysosomal acid \u03b2-glucocerebrosidase, whose activity is deficient in Gaucher disease (GD). In Drosophila, there are two GBA1 orthologs, Gba1a and Gba1b, and Gba1b is the bona fide GCase encoding gene. Several fly lines with different deletions in the Gba1b were studied in the past. However, since most GD-associated GBA1 mutations are point mutations, we created missense mutations homologous to the two most common GD mutations: the mild N370S mutation (D415S in Drosophila) and the severe L444P mutation (L494P in Drosophila), using the CRISPR-Cas9 technology. Flies homozygous for the D415S mutation (dubbed D370S hereafter) presented low GCase activity and substrate accumulation, which led to lysosomal defects, activation of the Unfolded Protein Response (UPR), inflammation\/neuroinflammation, and neurodegeneration along with earlier death compared to control flies. Surprisingly, the L494P (called L444P hereafter) flies presented higher GCase activity with fewer lysosomal defects and milder disease in comparison to that presented by the D370S homozygous flies. Treatment with ambroxol had a limited effect on all homozygous fly lines tested. Overall, our results underscore the differences between the fly and human GCase enzymes, as evidenced by the distinct phenotypic outcomes of mutations in flies compared to those observed in human GD patients.<\/jats:p>","DOI":"10.3390\/cells13191619","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T06:10:27Z","timestamp":1727417427000},"page":"1619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Functional Analysis of Human GBA1 Missense Mutations in Drosophila: Insights into Gaucher Disease Pathogenesis and Phenotypic Consequences"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9481-4480","authenticated-orcid":false,"given":"Aparna","family":"Kuppuramalingam","sequence":"first","affiliation":[{"name":"Shmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Or","family":"Cabasso","sequence":"additional","affiliation":[{"name":"Shmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3142-1126","authenticated-orcid":false,"given":"Mia","family":"Horowitz","sequence":"additional","affiliation":[{"name":"Shmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"},{"name":"Sagol School of Neuroscience, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0006-291X(65)90743-6","article-title":"Metabolism of glucocerebrosides II. 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