{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:42:52Z","timestamp":1788846172058,"version":"build-2803163510"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["102172\/B\/13\/Z"],"award-info":[{"award-number":["102172\/B\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is a rare neurodegenerative disorder characterized by progressive dementia and premature death. Four ANCL-causing mutations have been identified, all mapping to the DNAJC5 gene that encodes cysteine string protein \u03b1 (CSP\u03b1). Here, using Caenorhabditis elegans, we describe an animal model of ANCL in which disease-causing mutations are introduced into their endogenous chromosomal locus, thereby mirroring the human genetic disorder. This was achieved through CRISPR\/Cas9-mediated gene editing of dnj-14, the C. elegans ortholog of DNAJC5. The resultant homozygous ANCL mutant worms exhibited reduced lifespans and severely impaired chemotaxis, similar to isogenic dnj-14 null mutants. Importantly, these phenotypes were also seen in balanced heterozygotes carrying one wild-type and one ANCL mutant dnj-14 allele, mimicking the heterozygosity of ANCL patients. We observed a more severe chemotaxis phenotype in heterozygous ANCL mutant worms compared with haploinsufficient worms lacking one copy of CSP, consistent with a dominant-negative mechanism of action. Additionally, we provide evidence of CSP haploinsufficiency in longevity, as heterozygous null mutants exhibited significantly shorter lifespan than wild-type controls. The chemotaxis phenotype of dnj-14 null mutants was fully rescued by transgenic human CSP\u03b1, confirming the translational relevance of the worm model. Finally, a focused compound screen revealed that the anti-epileptic drug ethosuximide could restore chemotaxis in dnj-14 ANCL mutants to wild-type levels. This suggests that ethosuximide may have therapeutic potential for ANCL and demonstrates the utility of this C. elegans model for future larger-scale drug screening.<\/jats:p>","DOI":"10.1093\/hmg\/ddac263","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T17:54:24Z","timestamp":1666720464000},"page":"1772-1785","source":"Crossref","is-referenced-by-count":7,"title":["A <i>Caenorhabditis elegans<\/i> model of autosomal dominant adult-onset neuronal ceroid lipofuscinosis identifies ethosuximide as a potential therapeutic"],"prefix":"10.1093","volume":"32","author":[{"given":"Eleanor","family":"Barker","sequence":"first","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St Department of Molecular Physiology & Cell Signalling, , Liverpool L69 3BX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0346-1289","authenticated-orcid":false,"given":"Alan","family":"Morgan","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St Department of Molecular Physiology & Cell Signalling, , Liverpool L69 3BX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff W","family":"Barclay","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St Department of Molecular Physiology & Cell Signalling, , Liverpool L69 3BX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,10,25]]},"reference":[{"key":"2023051907041939900_ref1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jnen\/62.1.1","article-title":"The neuronal ceroid-lipofuscinoses","volume":"62","author":"Haltia","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2023051907041939900_ref2","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbadis.2019.165614","article-title":"The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research","volume":"1866","author":"Huber","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. basis Dis."},{"key":"2023051907041939900_ref3","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/cge.13829","article-title":"Autosomal dominant neuronal ceroid lipofuscinosis: clinical features and molecular basis","volume":"99","author":"Naseri","year":"2021","journal-title":"Clin. Genet."},{"key":"2023051907041939900_ref4","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ajhg.2011.07.003","article-title":"Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis","volume":"89","author":"Noskov\u00e1","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2023051907041939900_ref5","article-title":"Adult-onset neuronal ceroid lipofuscinosis with a novel DNAJC5 mutation exhibits aberrant protein palmitoylation","volume":"14","author":"Huang","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"2023051907041939900_ref6","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/cge.12020","article-title":"Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease","volume":"83","author":"Cadieux-Dion","year":"2013","journal-title":"Clin. Genet."},{"key":"2023051907041939900_ref7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s40478-015-0256-5","article-title":"Clinically early-stage CSP\u03b1 mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss","volume":"3","author":"Benitez","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"2023051907041939900_ref8","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1126\/science.8310297","article-title":"Paralysis and early death in cysteine string protein mutants of Drosophila","volume":"263","author":"Zinsmaier","year":"1994","journal-title":"Science"},{"key":"2023051907041939900_ref9","doi-asserted-by":"crossref","DOI":"10.1016\/j.pneurobio.2020.101758","article-title":"Cysteine string proteins","volume":"188","author":"Gundersen","year":"2020","journal-title":"Prog. Neurobiol."},{"key":"2023051907041939900_ref10","doi-asserted-by":"crossref","first-page":"4748","DOI":"10.1091\/mbc.e06-03-0183","article-title":"Dual role of the cysteine-string domain in membrane binding and palmitoylation-dependent sorting of the molecular chaperone cysteine-string protein","volume":"17","author":"Greaves","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"2023051907041939900_ref11","doi-asserted-by":"crossref","first-page":"25014","DOI":"10.1074\/jbc.M802140200","article-title":"Palmitoylation and membrane interactions of the neuroprotective chaperone cysteine-string protein","volume":"283","author":"Greaves","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2023051907041939900_ref12","doi-asserted-by":"crossref","first-page":"e26741","DOI":"10.1371\/journal.pone.0026741","article-title":"Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis","volume":"6","author":"Benitez","year":"2011","journal-title":"PLoS One"},{"key":"2023051907041939900_ref13","doi-asserted-by":"crossref","DOI":"10.1371\/annotation\/26d7eb64-ccd2-41db-b1aa-7cdc8c1eff95","article-title":"Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families","volume":"7","author":"Velinov","year":"2012","journal-title":"PLoS One"},{"key":"2023051907041939900_ref14","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/s41431-019-0567-2","article-title":"Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing","volume":"28","author":"Jedlickova","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"2023051907041939900_ref15","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.cell.2005.09.028","article-title":"\u03b1-Synuclein cooperates with CSP\u03b1 in preventing neurodegeneration","volume":"123","author":"Chandra","year":"2005","journal-title":"Cell"},{"key":"2023051907041939900_ref16","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/ncb2131","article-title":"CSP\u03b1 promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity","volume":"13","author":"Sharma","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"2023051907041939900_ref17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41421-018-0012-7","article-title":"DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins","volume":"4","author":"Xu","year":"2018","journal-title":"Cell Discov."},{"key":"2023051907041939900_ref18","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.15252\/embj.201593489","article-title":"DnaJ\/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins","volume":"35","author":"Fontaine","year":"2016","journal-title":"EMBO J."},{"key":"2023051907041939900_ref19","first-page":"1","article-title":"Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5\/CSP\u03b1 mutants causes lipofuscin accumulation","author":"Lee","year":"2022","journal-title":"Autophagy, in press"},{"key":"2023051907041939900_ref20","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/s41598-017-01115-6","article-title":"Neurons export extracellular vesicles enriched in cysteine string protein and misfolded protein cargo","volume":"7","author":"Deng","year":"2017","journal-title":"Sci. Rep."},{"key":"2023051907041939900_ref21","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1016\/j.bbadis.2014.07.009","article-title":"Oligomerization of cysteine string protein alpha mutants causing adult neuronal ceroid lipofuscinosis","volume":"1842","author":"Zhang","year":"2014","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"2023051907041939900_ref22","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s41594-020-0375-y","article-title":"Aggregation of mutant cysteine string protein-\u03b1 via Fe-S cluster binding is mitigated by iron chelators","volume":"27","author":"Naseri","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2023051907041939900_ref23","doi-asserted-by":"crossref","first-page":"37330","DOI":"10.1074\/jbc.M112.389098","article-title":"Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis","volume":"287","author":"Greaves","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023051907041939900_ref24","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41598-017-00036-8","article-title":"A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis","volume":"7","author":"Diez-Ardanuy","year":"2017","journal-title":"Sci. Rep."},{"key":"2023051907041939900_ref25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13065-015-0143-y","article-title":"Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases","volume":"9","author":"Chen","year":"2015","journal-title":"Chem. Cent. J."},{"key":"2023051907041939900_ref26","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.1093\/hmg\/ddu316","article-title":"Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol","volume":"23","author":"Kashyap","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2023051907041939900_ref27","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13024-015-0046-3","article-title":"Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16\/FOXO target gene expression","volume":"10","author":"Chen","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"2023051907041939900_ref28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s00359-002-0279-9","article-title":"Impairment of central pattern generation in Drosophila cysteine string protein mutants","volume":"188","author":"Barclay","year":"2002","journal-title":"J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol."},{"key":"2023051907041939900_ref29","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0896-6273(04)00190-4","article-title":"The synaptic vesicle protein CSP\u03b1 prevents presynaptic degeneration","volume":"42","author":"Fern\u00e1ndez-Chac\u00f3n","year":"2004","journal-title":"Neuron"},{"key":"2023051907041939900_ref30","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1139\/O09-124","article-title":"CSPalpha: the neuroprotective J protein","volume":"88","author":"Johnson","year":"2010","journal-title":"Biochem. 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Biol."},{"key":"2023051907041939900_ref33","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1007106","article-title":"Mutations in Caenorhabditis elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment","volume":"14","author":"Offenburger","year":"2018","journal-title":"PLoS Genet."},{"key":"2023051907041939900_ref34","article-title":"The Caenorhabditis elegans cysteine-string protein homologue DNJ-14 is dispensable for neuromuscular junction maintenance across ageing","volume":"222","author":"Mulcahy","year":"2019","journal-title":"J. Exp. Biol."},{"key":"2023051907041939900_ref35","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.46607","article-title":"A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism","volume":"8","author":"Imler","year":"2019","journal-title":"elife"},{"key":"2023051907041939900_ref36","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1534\/genetics.117.300119","article-title":"Ethanol stimulates locomotion via a G\u03b1s-signaling pathway in IL2 neurons in Caenorhabditis elegans","volume":"207","author":"Johnson","year":"2017","journal-title":"Genetics"},{"key":"2023051907041939900_ref37","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jneumeth.2018.09.004","article-title":"A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action","volume":"309","author":"Wong","year":"2018","journal-title":"J. Neurosci. 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Neurosci."},{"key":"2023051907041939900_ref45","doi-asserted-by":"crossref","first-page":"330","DOI":"10.4161\/auto.5618","article-title":"Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans","volume":"4","author":"Toth","year":"2008","journal-title":"Autophagy"},{"key":"2023051907041939900_ref46","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nchembio.380","article-title":"A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans","volume":"6","author":"Burns","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"2023051907041939900_ref47","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1534\/g3.118.200778","article-title":"CRISPR\/Cas9 methodology for the generation of knockout deletions in Caenorhabditis elegans","volume":"9","author":"Au","year":"2019","journal-title":"G3 (Bethesda)"},{"key":"2023051907041939900_ref48","article-title":"OASIS: online application for the survival analysis of lifespan assays performed in aging research","volume":"6","author":"Yang","year":"2011","journal-title":"PLoS One"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac263\/49424172\/ddac263.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/11\/1772\/50388838\/ddac263.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/11\/1772\/50388838\/ddac263.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T07:05:52Z","timestamp":1684479952000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/11\/1772\/6772468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,25]]},"references-count":48,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,10,25]]},"published-print":{"date-parts":[[2023,5,18]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac263","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6,1]]},"published":{"date-parts":[[2022,10,25]]}}}