{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T18:23:08Z","timestamp":1775845388725,"version":"3.50.1"},"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009017","name":"ALS Society of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009017","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009408","name":"Fondation Brain Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009408","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Intronic hexanucleotide repeat expansions in the\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene represent the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This expansion decreases\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expression in affected patients, indicating that loss of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    function (LOF) acts as a pathogenic mechanism. Several models using\n                    <jats:italic>Danio rerio<\/jats:italic>\n                    (zebrafish) for\n                    <jats:italic>C9orf72<\/jats:italic>\n                    depletion have been developed to explore disease mechanisms and the consequences of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    LOF. However, inconsistencies exist in reported phenotypes, and many have yet to be validated in stable germline ablation models. To address this, we created a zebrafish\n                    <jats:italic>C9orf72<\/jats:italic>\n                    knockout model using CRISPR\/Cas9. The\n                    <jats:italic>C9orf72<\/jats:italic>\n                    LOF model demonstrates, in a generally dose-dependent manner, increased larval mortality, persistent growth reduction, and motor deficits. Additionally, homozygous\n                    <jats:italic>C9orf72<\/jats:italic>\n                    LOF larvae exhibited mild overbranching of spinal motoneurons. To identify potential therapeutic compounds, we performed a screen on an established\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    (\n                    <jats:italic>C. elegans<\/jats:italic>\n                    )\n                    <jats:italic>C9orf72<\/jats:italic>\n                    homologue (\n                    <jats:italic>alfa-1<\/jats:italic>\n                    ) LOF model, identifying 12 compounds that enhanced motility, reduced neurodegeneration, and alleviated paralysis phenotypes. Motivated by the shared motor phenotype, 2 of those compounds were tested in our zebrafish\n                    <jats:italic>C9orf72<\/jats:italic>\n                    LOF model. Pizotifen malate was found to significantly improve motor deficits in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    LOF zebrafish larvae. We introduce a novel zebrafish\n                    <jats:italic>C9orf72<\/jats:italic>\n                    knockout model that exhibits phenotypic differences from depletion models, providing a valuable tool for\n                    <jats:italic>in vivo C9orf72<\/jats:italic>\n                    research and ALS therapeutic validation. Furthermore, we identify pizotifen malate as a promising compound for further preclinical evaluation.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0346613","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:33:39Z","timestamp":1775842419000},"page":"e0346613","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7303-3064","authenticated-orcid":true,"given":"Alexandre","family":"Emond","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl","family":"Laflamme","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3150-4052","authenticated-orcid":true,"given":"Martine","family":"Therrien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meijiang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2259-8835","authenticated-orcid":true,"given":"Claudia","family":"Maios","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Labarre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Drapeau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3333-2445","authenticated-orcid":true,"given":"J. Alex","family":"Parker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"issue":"3","key":"pone.0346613.ref001","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41573-022-00612-2","article-title":"Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation","volume":"22","author":"RJ Mead","year":"2023","journal-title":"Nat Rev Drug Discov"},{"issue":"2","key":"pone.0346613.ref002","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"M 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