{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:47:57Z","timestamp":1786978077001,"version":"build-2736575974"},"reference-count":74,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan\u2010\u03b1\u2010glucosaminide\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyltransferase (\n                    <jats:italic>HGSNAT<\/jats:italic>\n                    ; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep\u2013wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As\n                    <jats:italic>HGSNAT<\/jats:italic>\n                    is conserved in\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    , we now describe the creation and characterisation of the first\n                    <jats:italic>Drosophila<\/jats:italic>\n                    models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi\u2010mediated knockdown of\n                    <jats:italic>hgsnat<\/jats:italic>\n                    were confirmed to have a reduced level of HGSNAT transcripts and age\u2010dependent accumulation of heparan sulphate leading to engorgement of the endo\/lysosomal compartment. This resulted in abnormalities at the pre\u2010synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in\n                    <jats:italic>hgsnat<\/jats:italic>\n                    neuronal knockdown lines. Further, when\n                    <jats:italic>hgsnat<\/jats:italic>\n                    was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that\n                    <jats:italic>hgsnat<\/jats:italic>\n                    function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12712","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T21:36:44Z","timestamp":1705613804000},"page":"340-354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>\n                      <i>Drosophila melanogaster<\/i>\n                    <\/scp>\n                    models of\n                    <scp>MPS IIIC<\/scp>\n                    (\n                    <scp>\n                      <i>Hgsnat<\/i>\n                    <\/scp>\n                    \u2010deficiency) highlight the role of glia in disease presentation"],"prefix":"10.1002","volume":"47","author":[{"given":"Laura","family":"Hewson","sequence":"first","affiliation":[{"name":"Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani L.","family":"Webber","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Trim","sequence":"additional","affiliation":[{"name":"Proteomics, Metabolomics &amp; MS\u2010Imaging Core South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten F.","family":"Snel","sequence":"additional","affiliation":[{"name":"Proteomics, Metabolomics &amp; MS\u2010Imaging Core South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony O.","family":"Fedele","sequence":"additional","affiliation":[{"name":"Hopwood Centre for Neurobiology South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Hopwood","sequence":"additional","affiliation":[{"name":"Hopwood Centre for Neurobiology South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-9884","authenticated-orcid":false,"given":"Kim M.","family":"Hemsley","sequence":"additional","affiliation":[{"name":"Childhood Dementia Research Group, Flinders Health and Medical Research Institute Flinders University Bedford Park South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise V.","family":"O'Keefe","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22643"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.141150"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1086\/508068"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1086\/508294"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S57672"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2002.620512.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22092"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.69.3.403"},{"key":"e_1_2_7_10_1","first-page":"1","article-title":"Treatment of mucopolysaccharidosis type III (Sanfilippo syndrome)","volume":"1","author":"Meijer OLM","year":"2013","journal-title":"Expert Opin Orphan Drugs"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/apa.12169"},{"issue":"13","key":"e_1_2_7_12_1","first-page":"3742","article-title":"Non\u2010syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan\u2010alpha\u2010glucosaminide N\u2010acetyltransferase (HGSNAT)","volume":"24","author":"Haer\u2010Wigman L","year":"2015","journal-title":"Hum Mol Genet"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/13816810.2023.2245035"},{"key":"e_1_2_7_14_1","doi-asserted-by":"crossref","unstructured":"Schiff ER Daich Varela M et al. A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT the gene associated with Sanfilippo C mucopolysaccharidosis.Am J Med Genet C Semin Med Genet. 2020;184(3):631\u2010643.","DOI":"10.1002\/ajmg.c.31822"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2004.065482"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3565"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-013-9613-3"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00417"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2020-0742"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1067364"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2006-9S331"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm318"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13935"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.05.006"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.10.006"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30169-2"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr112"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-122313-085916"},{"key":"e_1_2_7_29_1","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1242\/dmm.025171","article-title":"Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC","volume":"9","author":"Marco S","year":"2016","journal-title":"Dis Model Mech"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu355"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20211860"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2018.01.020"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21286"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.09.011"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9488"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy126"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.104.026427"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00328"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.35574"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.27.534462"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(03)01005-2"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.036954"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr573"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4527-15.2016"},{"key":"e_1_2_7_45_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0004201","article-title":"Abeta42\u2010induced neurodegeneration via an age\u2010dependent autophagic\u2010lysosomal injury in Drosophila","volume":"4","author":"Ling D","year":"2009","journal-title":"PloS One"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02502"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1580103"},{"key":"e_1_2_7_48_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.1002563","article-title":"Spermidine suppresses age\u2010associated memory impairment by preventing adverse increase of presynaptic active zone size and release","volume":"14","author":"Gupta VK","year":"2016","journal-title":"PLoS Biol"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-08-034186-6.50008-6"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2016.36"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2004.08.019"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.05.005"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035787"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx058"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ker394"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-008-0838-5"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.20.10954"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.19469"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0381442"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111451"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09262-2"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175894"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.305888.117"},{"issue":"1438","key":"e_1_2_7_64_1","article-title":"Glial phagocytic receptors promote neuronal loss in adult Drosophila brain","volume":"29","author":"Hakim\u2010Mishnaevski K","year":"2019","journal-title":"Cell Rep"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2018.12.019"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2023.102689"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18291-1"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-017-0009-1"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016601"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.012385"},{"key":"e_1_2_7_71_1","doi-asserted-by":"crossref","unstructured":"Zhang M Strnatka D Donohue C Hallows JL Vincent I Erickson RP.\u00a0 Astrocyte\u2010only Npc1 reduces neuronal cholesterol and triples life span of Npc1\u2010\/\u2010 mice.J Neurosci Res. 2008;86(13):2848\u20102856.","DOI":"10.1002\/jnr.21730"},{"key":"e_1_2_7_72_1","doi-asserted-by":"crossref","unstructured":"Di Malta C Fryer JD Settembre C Ballabio A. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder.Proc Natl Acad Sci USA. 2012;109(35):E2334\u20102342.","DOI":"10.1073\/pnas.1209577109"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0255-22.2022"},{"key":"e_1_2_7_74_1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.50063","article-title":"Drosophila PSI controls circadian period and the phase of circadian behavior under temperature cycle via tim splicing","volume":"8","author":"Foley LE","year":"2019","journal-title":"Elife"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.118.300808"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12712","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T09:43:24Z","timestamp":1731059004000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":74,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1002\/jimd.12712"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12712","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,18]]},"assertion":[{"value":"2023-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}