{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:07:17Z","timestamp":1790701637907,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":271,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"University of Malta Research Seed Fund","id":[{"id":"https:\/\/ror.org\/03a62bv60","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Xjenza Malta Fusion R&I Research Excellence Programme 2023","award":["REP-2023-018"],"award-info":[{"award-number":["REP-2023-018"]}]},{"name":"Xjenza Malta Research Networking Scheme 2026","award":["RNS-2026-0030"],"award-info":[{"award-number":["RNS-2026-0030"]}]},{"name":"Tertiary Education Scholarship Scheme"},{"name":"Reach High II Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive motor neuron (MN) loss. Although rare pathogenic variants in the D-amino acid oxidase (DAO) gene have been proposed to cause familial ALS, inconsistent findings across mammalian models have hindered functional validation. Here, we establish and characterise a Drosophila model of DAO loss-of-function by targeting its highly conserved orthologue, Daao1. Constitutive Daao1 knockdown caused early developmental lethality, while surviving adult escapers exhibited profound flight and climbing impairments. Contrary to expectations, Daao1 deficiency did not elevate D-serine levels in larval or adult brains, and simultaneous knockdown of serine racemase (Srr), the enzyme responsible for D-serine synthesis, failed to rescue locomotor phenotypes. Tissue-specific silencing revealed that Daao1 is essential within both MNs and muscles, but not glia, for maintaining motor performance. RNA-seq of Daao1-deficient flies uncovered widespread transcriptional dysregulation affecting metabolism, peptide transport, immune activation and developmental pathways, accompanied by alternative splicing changes in genes required for neuronal morphology and synaptic organisation. Consistent with these molecular alterations, neuromuscular junctions (NMJs) displayed reduced axonal branching and bouton numbers, indicating disrupted neuromuscular connectivity. Remarkably, ubiquitous expression of human DAO rescued lethality and motor defects, demonstrating functional conservation and supporting a role for DAO in maintaining neuromuscular health. Together, our findings reveal a previously unrecognised, D-serine-independent role for DAO in neuromuscular integrity and provide functional evidence connecting DAO dysfunction to ALS-relevant phenotypes. The DAO-ALS Drosophila model provides a powerful platform for mechanistic studies and for evaluating human DAO variants of uncertain significance in ALS.<\/jats:p>","DOI":"10.1093\/hmg\/ddag093","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:59:30Z","timestamp":1789473570000},"source":"Crossref","is-referenced-by-count":0,"title":["Motor dysfunction phenotypes in a\n                    <i>drosophila<\/i>\n                    model validate\n                    <i>DAO<\/i>\n                    as an ALS gene"],"prefix":"10.1093","volume":"35","author":[{"given":"Sylvana","family":"Tabone","sequence":"first","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, Biomedical Sciences Building, University of Malta , Msida MSD 2080 ,","place":["Malta"]},{"name":"Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta , Msida MSD 2080 ,","place":["Malta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Cacciottolo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, Biomedical Sciences Building, University of Malta , Msida MSD 2080 ,","place":["Malta"]},{"name":"Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta , Msida MSD 2080 ,","place":["Malta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6150-1608","authenticated-orcid":false,"given":"Ruben J","family":"Cauchi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, Biomedical Sciences Building, University of Malta , Msida MSD 2080 ,","place":["Malta"]},{"name":"Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta , Msida MSD 2080 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