{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:01:56Z","timestamp":1772028116258,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T00:00:00Z","timestamp":1557792000000},"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":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in at least 13 different genes (called <jats:italic>CLN<\/jats:italic>s) underlie various forms of neuronal ceroid lipofuscinoses (NCLs), a group of the most common neurodegenerative lysosomal storage diseases. While inactivating mutations in the <jats:italic>CLN1<\/jats:italic> gene, encoding palmitoyl\u2010protein thioesterases\u20101 (PPT1), cause infantile NCL (INCL), those in the <jats:italic>CLN3<\/jats:italic> gene, encoding a protein of unknown function, underlie juvenile NCL (JNCL). PPT1 depalmitoylates S\u2010palmitoylated proteins (constituents of ceroid) required for their degradation by lysosomal hydrolases and PPT1\u2010deficiency causes lysosomal accumulation of autofluorescent ceroid leading to INCL. Because intracellular accumulation of ceroid is a characteristic of all NCLs, a common pathogenic link for these diseases has been suggested. It has been reported that <jats:italic>CLN3<\/jats:italic>\u2010mutations suppress the exit of cation\u2010independent mannose 6\u2010phosphate receptor (CI\u2010M6PR) from the trans Golgi network (TGN). Because CI\u2010M6PR transports soluble proteins such as PPT1 from the TGN to the lysosome, we hypothesized that <jats:italic>CLN3<\/jats:italic>\u2010mutations may cause lysosomal PPT1\u2010insufficiency contributing to JNCL pathogenesis. Here, we report that the lysosomes in <jats:italic>Cln3<\/jats:italic>\u2010mutant mice, which mimic JNCL, and those in cultured cells from JNCL patients, contain significantly reduced levels of Ppt1\u2010protein and Ppt1\u2010enzyme activity and progressively accumulate autofluorescent ceroid. Furthermore, in JNCL fibroblasts the V0a1 subunit of v\u2010ATPase, which regulates lysosomal acidification, is mislocalized to the plasma membrane instead of its normal location on lysosomal membrane. This defect dysregulates lysosomal acidification, as we previously reported in <jats:italic>Cln1<\/jats:italic><jats:sup>\n<jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, which mimic INCL. Our findings uncover a previously unrecognized role of CLN3 in lysosomal homeostasis and suggest that <jats:italic>CLN3<\/jats:italic>\u2010mutations causing lysosomal Ppt1\u2010insuffiiciency may at least in part contribute to JNCL pathogenesis.<\/jats:p>","DOI":"10.1002\/jimd.12106","type":"journal-article","created":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T10:29:46Z","timestamp":1556274586000},"page":"944-954","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<i>Cln3<\/i>\u2010mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl\u2010protein thioesterases\u20101 (Ppt1)\u2010protein and Ppt1\u2010enzyme activity in the lysosome"],"prefix":"10.1002","volume":"42","author":[{"given":"Abhilash P.","family":"Appu","sequence":"first","affiliation":[{"name":"Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria B.","family":"Bagh","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamal","family":"Sadhukhan","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avisek","family":"Mondal","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney","family":"Casey","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4445-5464","authenticated-orcid":false,"given":"Anil B.","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200421476"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.11.014"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.04.027"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.05.011"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70194-1"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30368-5"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/376584a0"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)31641-1"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(73)90075-0"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90274-0"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2788"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2005.08.001"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.19.10046"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)41567-0"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.2217\/clp.11.70"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2008.00807.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.10.016"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2010.12.011"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2660(01)45008-5"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.1999.2809"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00462.2010"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi451"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D011106"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809161200"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14612"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14587"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1207056"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2272"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251485198"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.02.010"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.018"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0014-2956.2001.02530.x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2008.00814.x"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.132.4.577"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau0629"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0901281"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.11.001"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12632"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.09.023"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1861-8"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01020"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3526"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12106","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12106","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T12:59:11Z","timestamp":1694091551000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,14]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["10.1002\/jimd.12106"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12106","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,14]]},"assertion":[{"value":"2018-11-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}