{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T01:09:33Z","timestamp":1787274573434,"version":"build-2736575974"},"reference-count":73,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"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":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inactivating mutations in the <jats:italic>PPT1<\/jats:italic> gene encoding palmitoyl\u2010protein thioesterase\u20101 (PPT1) underlie the CLN1 disease, a devastating neurodegenerative lysosomal storage disorder. The mechanism of pathogenesis underlying CLN1 disease has remained elusive. PPT1 is a lysosomal enzyme, which catalyzes the removal of palmitate from S\u2010palmitoylated proteins (constituents of ceroid lipofuscin) facilitating their degradation and clearance by lysosomal hydrolases. Thus, it has been proposed that Ppt1\u2010deficiency leads to lysosomal accumulation of ceroid lipofuscin leading to CLN1 disease. While S\u2010palmitoylation is catalyzed by palmitoyl acyltransferases (called ZDHHCs), palmitoyl\u2010protein thioesterases (PPTs) depalmitoylate these proteins. We sought to determine the mechanism by which Ppt1\u2010deficiency may impair lysosomal degradative function leading to infantile neuronal ceroid lipofuscinosis pathogenesis. Here, we report that in <jats:italic>Ppt1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, which mimic <jats:italic>CLN1<\/jats:italic> disease, low level of inositol 3\u2010phosphate receptor\u20101 (IP3R1) that mediates Ca<jats:sup>++<\/jats:sup> transport from the endoplasmic reticulum to the lysosome dysregulated lysosomal Ca<jats:sup>++<\/jats:sup> homeostasis. Intriguingly, the transcription factor nuclear factor of activated T\u2010cells, cytoplasmic 4 (NFATC4), which regulates <jats:italic>IP3R1\u2010<\/jats:italic>expression, required S\u2010palmitoylation for trafficking from the cytoplasm to the nucleus. We identified two palmitoyl acyltransferases, ZDHHC4 and ZDHHC8, which catalyzed S\u2010palmitoylation of NFATC4. Notably, in <jats:italic>Ppt1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, reduced ZDHHC4 and ZDHHC8 levels markedly lowered S\u2010palmitoylated NFATC4 (active) in the nucleus, which inhibited <jats:italic>IP3R1<\/jats:italic>\u2010expression, thereby dysregulating lysosomal Ca<jats:sup>++<\/jats:sup> homeostasis. Consequently, Ca<jats:sup>++<\/jats:sup>\u2010dependent lysosomal enzyme activities were markedly suppressed. Impaired lysosomal degradative function impaired autophagy, which caused lysosomal storage of undigested cargo. Importantly, IP3R1\u2010overexpression in <jats:italic>Ppt1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse fibroblasts ameliorated this defect. Our results reveal a previously unrecognized role of <jats:italic>Ppt1<\/jats:italic> in regulating lysosomal Ca<jats:sup>++<\/jats:sup> homeostasis and suggest that this defect contributes to pathogenesis of CLN1 disease.<\/jats:p>","DOI":"10.1002\/jimd.12485","type":"journal-article","created":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T12:08:22Z","timestamp":1644667702000},"page":"635-656","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Ppt1\u2010deficiency dysregulates lysosomal Ca<sup>++<\/sup> homeostasis contributing to pathogenesis in a mouse model of <scp><i>CLN1<\/i><\/scp> disease"],"prefix":"10.1002","volume":"45","author":[{"given":"Avisek","family":"Mondal","sequence":"first","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhilash P.","family":"Appu","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamal","family":"Sadhukhan","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria B.","family":"Bagh","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael M.","family":"Previde","sequence":"additional","affiliation":[{"name":"Section on Cellular Signaling Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sriparna","family":"Sadhukhan","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanko","family":"Stojilkovic","sequence":"additional","affiliation":[{"name":"Section on Cellular Signaling Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4445-5464","authenticated-orcid":false,"given":"Anil B.","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.28.030166.002251"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0300-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-122313-085916"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201208152"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1423"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2011.03.010"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3114"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-070815-014031"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20170055"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200421476"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2004.tb00499.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.165570"},{"key":"e_1_2_10_14_1","first-page":"1882","article-title":"NCL disease mechanisms","volume":"2013","author":"Palmer DN","year":"1832","journal-title":"Biochim Biophys Acta"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.11.014"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30368-5"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.05.011"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1974.tb04183.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/376584a0"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)41567-0"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.19.10046"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4157(89)90013-0"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400006"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2788"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201008160"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0465-x"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/09687680802629329"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1086\/513609"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251485198"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.02.010"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi451"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18051024"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-15-0602-4_7"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2018.04.049"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.064"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15887"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1417176111"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011353"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12242"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(99)00115-7"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1876"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.796920"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2001.5155"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14612"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth947"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12152-2"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/44378"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5343.1638"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/382370a0"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14545"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells7110188"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.11.3892-3904.2002"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.12.005"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19123820"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzn039"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D011106"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.02.016"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810611105"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2016.09.001"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-018-0523-x"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0431-y"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011929"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1375"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2204"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3232"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0185-4"},{"key":"e_1_2_10_67_1","first-page":"56","article-title":"Lysosomal calcium in neurodegeneration","volume":"5","author":"Feng X","year":"2016","journal-title":"Messenger (Los Angel)"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctm.2019.08.001"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00421-4"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.754045"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70142-5"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1712649"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mcb.2014.10.031"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1281"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12485","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12485","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12485","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T08:02:42Z","timestamp":1692777762000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,17]]},"references-count":73,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1002\/jimd.12485"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12485","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,17]]},"assertion":[{"value":"2021-10-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}