{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:23:23Z","timestamp":1791991403941,"version":"4.4.0"},"reference-count":56,"publisher":"Wiley","issue":"5-6","license":[{"start":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T00:00:00Z","timestamp":1685232000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005468","name":"Batten Disease Support and Research Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005468","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Developmental Neurobiology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end\u2010stage disease at \u226424 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto\u2010occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end\u2010stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near\u2010linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep\u2014presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)\u2014beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages.<\/jats:p>","DOI":"10.1002\/dneu.22918","type":"journal-article","created":{"date-parts":[[2023,5,29]],"date-time":"2023-05-29T05:21:22Z","timestamp":1685337682000},"page":"127-142","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)"],"prefix":"10.1002","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4801-2804","authenticated-orcid":false,"given":"Nadia L.","family":"Mitchell","sequence":"first","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Lincoln New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina N.","family":"Russell","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Lincoln New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7644-6816","authenticated-orcid":false,"given":"Graham K.","family":"Barrell","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Lincoln New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5520-6597","authenticated-orcid":false,"given":"Imke","family":"Tammen","sequence":"additional","affiliation":[{"name":"Faculty of Science Sydney School of Veterinary Science The University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9703-5351","authenticated-orcid":false,"given":"David N.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences Lincoln University  Lincoln New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.401"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0887\u20108994(92)90032\u2010T"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2020.116826"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI130955"},{"key":"e_1_2_9_6_1","unstructured":"Beganovic D. F. Sutton A. Cronin G. M. Hughes K. Zaki S. Thomson P. &Tammen I.(2012).Behavioural studies and magnetic resonance imaging in the Merino sheep NCL model. In13th International Conference on Neuronal Ceroid Lipofuscinoses (Batten Disease) London UK P18."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2006.04.010"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410330408"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.165571"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.12.159"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751\u20100813.2002.tb10847.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.applanim.2015.11.012"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201045859\u20109"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335\u2010017\u20109687\u20106"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.09.006"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.754045"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.1999.2808"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.1.1"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400643200"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.11.001"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/00480169.2002.36311"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/00480169.1992.35711"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102990.1989.tb01236.x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750\u20103639.2006.00002.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263\u2010019\u201000620\u20108"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.66.1453"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvim.13971"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh312"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1388\u20102457(02)00200\u20106"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165772"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj8633"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010014\u20107553\u2010y"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102990.1985.tb00025.x"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22878"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075963"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.015"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1100\/2012\/383174"},{"key":"e_1_2_9_38_1","unstructured":"Mohd Ismail I. F.(2014).Identification of a novel mutation in the CLN6 gene causing neuronal ceroid lipofuscinosis in South Hampshire sheep(PhD thesis).University of Sydney.http:\/\/hdl.handle.net\/2123\/14579"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/med\/9780199590018.001.0001"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2004.04.042"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078694"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcac339"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1684\/epd.2016.0844"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.06.004"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.01.025"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.06.014"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0887\u20108994(01)00284\u20103"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1096"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dib.2021.107188"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132331"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1712649"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.13473"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2021.1972255"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1053\/ejpn.2000.0432"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2006.09.004"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072\u2010199704000\u201000005"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320570252"}],"container-title":["Developmental Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dneu.22918","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T02:09:20Z","timestamp":1694743760000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/dneu.22918"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,28]]},"references-count":56,"journal-issue":{"issue":"5-6","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1002\/dneu.22918"],"URL":"https:\/\/doi.org\/10.1002\/dneu.22918","archive":["Portico"],"relation":{},"ISSN":["1932-8451","1932-846X"],"issn-type":[{"value":"1932-8451","type":"print"},{"value":"1932-846X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,28]]},"assertion":[{"value":"2022-11-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}