PMID- 31025705 OWN - NLM STAT- MEDLINE DCOM- 20200916 LR - 20210109 IS - 1573-2665 (Electronic) IS - 0141-8955 (Print) IS - 0141-8955 (Linking) VI - 42 IP - 5 DP - 2019 Sep TI - Cln3-mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl-protein thioesterases-1 (Ppt1)-protein and Ppt1-enzyme activity in the lysosome. PG - 944-954 LID - 10.1002/jimd.12106 [doi] AB - Mutations in at least 13 different genes (called CLNs) underlie various forms of neuronal ceroid lipofuscinoses (NCLs), a group of the most common neurodegenerative lysosomal storage diseases. While inactivating mutations in the CLN1 gene, encoding palmitoyl-protein thioesterases-1 (PPT1), cause infantile NCL (INCL), those in the CLN3 gene, encoding a protein of unknown function, underlie juvenile NCL (JNCL). PPT1 depalmitoylates S-palmitoylated proteins (constituents of ceroid) required for their degradation by lysosomal hydrolases and PPT1-deficiency 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 CLN3-mutations suppress the exit of cation-independent mannose 6-phosphate receptor (CI-M6PR) from the trans Golgi network (TGN). Because CI-M6PR transports soluble proteins such as PPT1 from the TGN to the lysosome, we hypothesized that CLN3-mutations may cause lysosomal PPT1-insufficiency contributing to JNCL pathogenesis. Here, we report that the lysosomes in Cln3-mutant mice, which mimic JNCL, and those in cultured cells from JNCL patients, contain significantly reduced levels of Ppt1-protein and Ppt1-enzyme activity and progressively accumulate autofluorescent ceroid. Furthermore, in JNCL fibroblasts the V0a1 subunit of v-ATPase, 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 Cln1 (-/-) mice, which mimic INCL. Our findings uncover a previously unrecognized role of CLN3 in lysosomal homeostasis and suggest that CLN3-mutations causing lysosomal Ppt1-insuffiiciency may at least in part contribute to JNCL pathogenesis. CI - Published 2019. This article is a U.S. Government work and is in the public domain in the USA. FAU - Appu, Abhilash P AU - Appu AP AD - Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. FAU - Bagh, Maria B AU - Bagh MB AD - Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. FAU - Sadhukhan, Tamal AU - Sadhukhan T AD - Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. FAU - Mondal, Avisek AU - Mondal A AD - Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. FAU - Casey, Sydney AU - Casey S AD - Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. FAU - Mukherjee, Anil B AU - Mukherjee AB AUID- ORCID: 0000-0003-4445-5464 AD - Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. LA - eng GR - Z99 HD999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20190514 PL - United States TA - J Inherit Metab Dis JT - Journal of inherited metabolic disease JID - 7910918 RN - 0 (CLN3 protein, human) RN - 0 (CLN3 protein, mouse) RN - 0 (Membrane Glycoproteins) RN - 0 (Molecular Chaperones) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) SB - IM MH - Animals MH - Cell Line MH - Cells, Cultured MH - Disease Models, Animal MH - Gene Expression Regulation MH - Humans MH - Lysosomes/*enzymology MH - Membrane Glycoproteins/*genetics MH - Mice MH - Mice, Inbred C57BL MH - Molecular Chaperones/*genetics MH - Mutation MH - Neuronal Ceroid-Lipofuscinoses/*genetics/pathology MH - Thiolester Hydrolases/genetics/*metabolism PMC - PMC6739123 MID - NIHMS1027755 OTO - NOTNLM OT - batten disease OT - infantile neuronal ceroid lipofuscinosis OT - juvenile neuronal ceroid lipofuscinosis OT - lysosomal storage disease OT - neurodegeneration OT - palmitoyl-protein thioesterase-1 COIS- CONFLICT OF INTEREST Abhilash P. Appu, Maria B. Bagh, Tamal Sadhukhan, Avisek Mondal, Sydney Casey and Anil B. Mukherjee declare that they have no conflict of interest. EDAT- 2019/04/27 06:00 MHDA- 2020/09/17 06:00 PMCR- 2020/09/01 CRDT- 2019/04/27 06:00 PHST- 2018/11/28 00:00 [received] PHST- 2019/03/13 00:00 [revised] PHST- 2019/04/25 00:00 [accepted] PHST- 2019/04/27 06:00 [pubmed] PHST- 2020/09/17 06:00 [medline] PHST- 2019/04/27 06:00 [entrez] PHST- 2020/09/01 00:00 [pmc-release] AID - 10.1002/jimd.12106 [doi] PST - ppublish SO - J Inherit Metab Dis. 2019 Sep;42(5):944-954. doi: 10.1002/jimd.12106. Epub 2019 May 14.