{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:18:30Z","timestamp":1785410310128,"version":"3.56.0"},"reference-count":16,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"NIH\/NINDS","award":["K08NS123552-01"],"award-info":[{"award-number":["K08NS123552-01"]}]},{"name":"CureAP4 Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Objective: Hereditary spastic paraplegia type 47 (SPG47) is caused by biallelic loss-of-function variants in the AP4B1 gene, leading to neurodevelopmental and progressive motor impairment. This study aimed to generate and characterize a zebrafish (Danio rerio) model of SPG47 to investigate the role of ap4b1 in neurodevelopment and motor function. Methods: We employed CRISPR\/Cas9 gene-editing to generate a stable ap4b1\u2212\/\u2212 zebrafish line. Behavioral, morphological, and motor function analyses were performed, including survival under stress conditions, spontaneous locomotor activity, light\u2013dark transition assays, and coiling behavior. Axonal length was assessed via immunofluorescence targeting spinal motor neurons. Seizure susceptibility was evaluated using a PTZ paradigm. Results: ap4b1\u2212\/\u2212 zebrafish exhibited significantly reduced axonal length of spinal motor neurons, impaired motor function, and developmental malformations, including brachycephaly, reduced body length, bent spines, and craniofacial defects. Increased tail coiling and reduced spontaneous activity were observed in larvae, alongside absent habituation to light\u2013dark stimuli. Under stress conditions, survival rates were significantly lower in the knockout group compared to controls. Despite early hyperexcitability, no significant increase in PTZ-induced seizures was observed. Interpretation: This study characterizes an ap4b1\u2212\/\u2212 zebrafish model that recapitulates some phenotypes of SPG47, including motor deficits and morphological abnormalities. These findings support the utility of zebrafish for studying AP-4 deficiency and provide a platform for investigating the molecular mechanisms underlying SPG47.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf056","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T18:10:21Z","timestamp":1745431821000},"page":"1034-1039","source":"Crossref","is-referenced-by-count":3,"title":["<i>ap4b1<\/i>\n          \u2212\/\u2212 zebrafish demonstrate morphological and motor abnormalities"],"prefix":"10.1093","volume":"34","author":[{"given":"Helena","family":"Rosengarten","sequence":"first","affiliation":[{"name":"Movement Disorders Program, Department of Neurology & The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School , 300 Longwood Avenue, Boston, MA 02115 ,","place":["United States"]},{"name":"Department of Pediatric Neurology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin , Mittelallee 9, 13353 Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology & The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School , 300 Longwood Avenue, Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo-Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology & The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School , 300 Longwood Avenue, Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology & The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School , 300 Longwood Avenue, Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"2025060505164583900_ref1","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/S1474-4422(19)30235-2","article-title":"Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches","volume":"18","author":"Shribman","year":"2019","journal-title":"Lancet Neurol"},{"key":"2025060505164583900_ref2","doi-asserted-by":"crossref","first-page":"e1942","DOI":"10.1212\/WNL.0000000000012836","article-title":"Systematic analysis of brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia","volume":"97","author":"Ebrahimi-Fakhari","year":"2021","journal-title":"Neurology"},{"key":"2025060505164583900_ref3","volume-title":"GeneReviews\u00ae [Internet]"},{"key":"2025060505164583900_ref4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/ajmg.a.38561","article-title":"Clinical and genetic characterization of AP4B1-associated SPG47","volume":"176","author":"Ebrahimi-Fakhari","year":"2018","journal-title":"Am J Med Genet A"},{"key":"2025060505164583900_ref5","first-page":"2929","article-title":"Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia","volume":"143","author":"Ebrahimi-Fakhari","year":"2020","journal-title":"Brain"},{"key":"2025060505164583900_ref6","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1042\/BST20190664","article-title":"The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia","volume":"48","author":"Mattera","year":"2020","journal-title":"Biochem Soc Trans"},{"key":"2025060505164583900_ref7","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1093\/hmg\/ddz310","article-title":"Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking","volume":"29","author":"Behne","year":"2020","journal-title":"Hum Mol Genet"},{"key":"2025060505164583900_ref8","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/s41467-022-28609-w","article-title":"AP-4-mediated axonal transport controls endocannabinoid production in neurons","volume":"13","author":"Davies","year":"2022","journal-title":"Nat Commun"},{"key":"2025060505164583900_ref9","doi-asserted-by":"crossref","first-page":"E10697","DOI":"10.1073\/pnas.1717327114","article-title":"AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation","volume":"114","author":"Mattera","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025060505164583900_ref10","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1080\/15548627.2019.1615302","article-title":"Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome","volume":"16","author":"Ivankovic","year":"2020","journal-title":"Autophagy"},{"key":"2025060505164583900_ref11","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1038\/s41467-018-06172-7","article-title":"AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A","volume":"9","author":"Davies","year":"2018","journal-title":"Nat Commun"},{"key":"2025060505164583900_ref12","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1002\/acn3.51018","article-title":"Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52","volume":"7","author":"D'Amore","year":"2020","journal-title":"Ann Clin Transl Neurol"},{"key":"2025060505164583900_ref13","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/s41467-023-44264-1","article-title":"High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia","volume":"15","author":"Saffari","year":"2024","journal-title":"Nat Commun"},{"key":"2025060505164583900_ref14","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22073472","article-title":"Genotype to phenotype: CRISPR gene editing reveals genetic compensation as a mechanism for phenotypic disjunction of Morphants and mutants","volume":"22","author":"Salanga","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2025060505164583900_ref15","doi-asserted-by":"crossref","first-page":"fcac335","DOI":"10.1093\/braincomms\/fcac335","article-title":"Ap4b1-knockout mouse model of hereditary spastic paraplegia type 47 displays motor dysfunction, aberrant brain morphology and ATG9A mislocalization","volume":"5","author":"Scarrott","year":"2023","journal-title":"Brain Commun"},{"key":"2025060505164583900_ref16","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1038\/s44321-024-00148-5","article-title":"Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47","volume":"16","author":"Wiseman","year":"2024","journal-title":"EMBO Mol Med"}],"container-title":["Human Molecular 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