{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T06:43:07Z","timestamp":1776408187354,"version":"3.51.2"},"reference-count":47,"publisher":"The Company of Biologists","issue":"6","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Parkinson's UK","award":["G1404"],"award-info":[{"award-number":["G1404"]}]},{"name":"Parkinson's UK","award":["G1704"],"award-info":[{"award-number":["G1704"]}]},{"name":"Medical Research Council","award":["MR\/R011354\/1"],"award-info":[{"award-number":["MR\/R011354\/1"]}]},{"name":"Medical Research Council","award":["MR\/M006646\/1"],"award-info":[{"award-number":["MR\/M006646\/1"]}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/S010386\/1"],"award-info":[{"award-number":["BB\/S010386\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100022572","name":"NIHR Sheffield Biomedical Research Centre","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022572","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000765","name":"University College London","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000765","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Niemann-Pick UK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo.<\/jats:p>","DOI":"10.1242\/dmm.049954","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T08:55:55Z","timestamp":1679561755000},"source":"Crossref","is-referenced-by-count":4,"title":["Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency"],"prefix":"10.1242","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2055-1187","authenticated-orcid":false,"given":"Marcus","family":"Keatinge","sequence":"first","affiliation":[{"name":"Bateson Centre, Firth Court, University of Sheffield 1 , Western Bank, Sheffield S10 2TN , UK"},{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield 2 , 385a Glossop Road, Sheffield S10 2HQ , UK"},{"name":"Centre for Discovery Brain Sciences 3 , Chancellor's Building, The University of Edinburgh, Edinburgh EH16 4TJ , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew E.","family":"Gegg","sequence":"additional","affiliation":[{"name":"UCL Queen Square Institute of Neurology 4 Department of Clinical and Movement Neurosciences , , London NW3 2PF , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Watson","sequence":"additional","affiliation":[{"name":"Bateson Centre, Firth Court, University of Sheffield 1 , Western Bank, Sheffield S10 2TN , UK"},{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield 2 , 385a Glossop Road, Sheffield S10 2HQ , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Mortiboys","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield 2 , 385a Glossop Road, Sheffield S10 2HQ , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Bateson Centre, Firth Court, University of Sheffield 1 , Western Bank, Sheffield S10 2TN , UK"},{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield 2 , 385a Glossop Road, Sheffield S10 2HQ , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Dunning","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield 2 , 385a Glossop Road, Sheffield S10 2HQ , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"Ailani","sequence":"additional","affiliation":[{"name":"Bateson Centre, Firth Court, University of Sheffield 1 , Western Bank, Sheffield S10 2TN , UK"},{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield 2 , 385a Glossop Road, Sheffield S10 2HQ , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai","family":"Bui","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company 5 , Drop Code 1940, Indianapolis, IN 46285 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"van Rens","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center 6 Department of Laboratory Medicine, Translational Metabolic Laboratory , , Nijmegen NL-6525 GA , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk J.","family":"Lefeber","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center 6 Department of Laboratory Medicine, Translational Metabolic Laboratory , , Nijmegen NL-6525 GA , The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre 7 Department of Neurology , , Nijmegen NL-6525 GA , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony H. 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