{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:23:21Z","timestamp":1791991401555,"version":"4.4.0"},"reference-count":109,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,1,16]],"date-time":"2021-01-16T00:00:00Z","timestamp":1610755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited childhood neurodegenerative disorders. In addition to the accumulation of auto\u2010fluorescent storage material in lysosomes, NCLs are largely characterised by region\u2010specific neuroinflammation that can predict neuron loss. These phenotypes suggest alterations in the extracellular environment\u2014making the secretome an area of significant interest. This study investigated the secretome in the CLN6 (ceroid\u2010lipofuscinosis neuronal protein 6) variant of NCL. To investigate the CLN6 secretome, we co\u2010cultured neurons and glia isolated from <jats:italic>Cln6<jats:sup>nclf<\/jats:sup> or Cln6<jats:sup>\u00b1<\/jats:sup><\/jats:italic> mice, and utilised mass spectrometry to compare protein constituents of conditioned media. The significant changes noted in cathepsin enzymes, were investigated further via western blotting and enzyme activity assays. Viral\u2010mediated gene therapy was used to try and rescue the wild\u2010type phenotype and restore the secretome\u2014both in vitro in co\u2010cultures and in vivo in mouse plasma. In <jats:italic>Cln6<jats:sup>nclf<\/jats:sup><\/jats:italic> cells, proteomics revealed a marked increase in catabolic and cytoskeletal\u2010associated proteins\u2014revealing new similarities between the pathogenic signatures of NCLs with other neurodegenerative disorders. These changes were, in part, corrected by gene therapy intervention, suggesting these proteins as candidate in vitro biomarkers. Importantly, these in vitro changes show promise for in vivo translation, with Cathepsin L (CTSL) activity reduced in both co\u2010cultures and <jats:italic>Cln6<jats:sup>nclf<\/jats:sup><\/jats:italic> plasma samples post gene\u2010therapy. This work suggests the secretome plays a role in CLN6 pathogenesis and highlights its potential use as an in vitro model. Proteomic changes present a list of candidate biomarkers for monitoring disease and assessing potential therapeutics in future studies.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15285-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15285","type":"journal-article","created":{"date-parts":[[2020,12,26]],"date-time":"2020-12-26T04:25:51Z","timestamp":1608956751000},"page":"764-780","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["An altered secretome is an early marker of the pathogenesis of CLN6 Batten disease"],"prefix":"10.1111","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-2749","authenticated-orcid":false,"given":"Hannah L.","family":"Best","sequence":"first","affiliation":[{"name":"Department of Biochemistry School of Biomedical Sciences Brain Health Research Centre University of Otago Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0048-8838","authenticated-orcid":false,"given":"Alison J.","family":"Clare","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Biomedical Sciences Brain Health Research Centre University of Otago Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstin O.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Biomedical Sciences Brain Health Research Centre University of Otago Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hollie E.","family":"Wicky","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Biomedical Sciences Brain Health Research Centre University of Otago Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7142-0040","authenticated-orcid":false,"given":"Stephanie M.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Biomedical Sciences Brain Health Research Centre University of Otago Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2015.2794"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.09.056"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0036-z"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081096"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.11.014"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.03.052"},{"key":"e_1_2_11_8_1","first-page":"4118","article-title":"A CLN6\u2010CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer","volume":"130","author":"Bajaj L.","year":"2020","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21399"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0201844"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182a4a577"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzh037"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22032"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.01.001"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.02.010"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00417"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.06.015"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017118"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1385\/MN:28:1:51"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.05.014"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.07.012"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn923"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy076"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddiscovery.2016.12"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/pr900248y"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14346"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.30802\/AALAS-JAALAS-18-000094"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09612"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112632299"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2013_226"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1053\/eipn.2000.0464"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0014-2956.2001.02530.x"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2015.00178"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2006.179"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt036"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109572"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.20134804"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2006.00002.x"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69052026.x"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.2217\/fnl.12.68"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.213686"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.2849"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.04995.x"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.11.012"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2012-111604"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00146.x"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2018.06.014"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz210"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-18-06898.2000"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)61253-9"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21029"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2011.026"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-75"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a035311"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055983"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2018.02.014"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-10-83"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160501"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1933-9"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1500937112"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400764"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2018.00045"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2008.00807.x"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp1019"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.165559"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.05.011"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05836.x"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078694"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.06.004"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201407077"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.05.014"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1513-1"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009373"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5332.1684"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.05.018"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag2590"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2011.08.016"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-017-1934-z"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R046896"},{"key":"e_1_2_11_81_1","first-page":"50079","article-title":"Isolation and culture of mouse cortical astrocytes","author":"Schildge S.","year":"2013","journal-title":"Journal of Visualized Experiments: Jove"},{"key":"e_1_2_11_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.04.008"},{"key":"e_1_2_11_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200401054"},{"key":"e_1_2_11_84_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA119.001587"},{"key":"e_1_2_11_85_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201200205"},{"key":"e_1_2_11_86_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20163893"},{"key":"e_1_2_11_87_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph12020087"},{"key":"e_1_2_11_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.07.084"},{"key":"e_1_2_11_89_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw937"},{"key":"e_1_2_11_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2006.06.002"},{"key":"e_1_2_11_91_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035493"},{"key":"e_1_2_11_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2003.11.003"},{"key":"e_1_2_11_93_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.772403"},{"key":"e_1_2_11_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2012.09.013"},{"key":"e_1_2_11_95_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13104-017-2940-y"},{"key":"e_1_2_11_96_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3085-18.2019"},{"key":"e_1_2_11_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2011.10.002"},{"key":"e_1_2_11_98_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2004.tb00077.x"},{"key":"e_1_2_11_99_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2009.173419"},{"key":"e_1_2_11_100_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e02-01-0031"},{"key":"e_1_2_11_101_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq273"},{"key":"e_1_2_11_102_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.371641"},{"key":"e_1_2_11_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.03.017"},{"key":"e_1_2_11_104_1","first-page":"NS20190001","article-title":"Modulation of CRMP2 via (S)\u2010Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6\u2010Batten disease","volume":"3","author":"White K. A.","year":"2019","journal-title":"Health Psychol. Behavioral Medicine"},{"key":"e_1_2_11_105_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1322"},{"key":"e_1_2_11_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.03.019"},{"key":"e_1_2_11_107_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a022396"},{"key":"e_1_2_11_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01326-4"},{"key":"e_1_2_11_109_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802502"},{"key":"e_1_2_11_110_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0997-871"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.15285","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.15285","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.15285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T03:14:42Z","timestamp":1693278882000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.15285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,16]]},"references-count":109,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1111\/jnc.15285"],"URL":"https:\/\/doi.org\/10.1111\/jnc.15285","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,16]]},"assertion":[{"value":"2020-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}