title: Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model.
abstract: Defective lysosomal acidification contributes to virtually all lysosomal storage disorders (LSDs) and to common neurodegenerative diseases like Alzheimer's and Parkinson's. Despite its fundamental importance, the mechanism(s) underlying this defect remains unclear. The v-ATPase, a multisubunit protein complex composed of cytosolic V1-sector and lysosomal membrane-anchored V0-sector, regulates lysosomal acidification. Mutations in the CLN1 gene, encoding PPT1, cause a devastating neurodegenerative LSD, INCL. Here we report that in Cln1-/-mice, which mimic INCL, reduced v-ATPase activity correlates with elevated lysosomal pH. Moreover, v-ATPase subunit a1 of the V0 sector (V0a1) requires palmitoylation for interacting with adaptor protein-2 (AP-2) and AP-3, respectively, for trafficking to the lysosomal membrane. Notably, treatment of Cln1-/-mice with a thioesterase (Ppt1)-mimetic, NtBuHA, ameliorated this defect. Our findings reveal an unanticipated role of Cln1 in regulating lysosomal targeting of V0a1 and suggest that varying factors adversely affecting v-ATPase function dysregulate lysosomal acidification in other LSDs and common neurodegenerative diseases.
authors.affiliation: Section on Developmental Genetics, PEMG, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Bagh
authors.affiliation: Section on Developmental Genetics, PEMG, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Section on Developmental Genetics, PEMG, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Goutam
authors.initials: G
authors.lastname: Chandra
authors.affiliation: Section on Developmental Genetics, PEMG, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: MolBox LLC, 8115 Fenton Street #304, Silver Spring, Maryland 20910, USA.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
authors.affiliation: Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Aiyi
authors.initials: A
authors.lastname: Liu
authors.affiliation: Section on Developmental Genetics, PEMG, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D011992:Endosomes / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D006898:Hydroxylamines / Q000627:therapeutic use*; D054878:Lipoylation; D016464:Lysosomal Storage Diseases / Q000188:drug therapy / Q000201:enzymology*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D011897:Random Allocation; D013869:Thiolester Hydrolases / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D033962:Adaptor Protein Complex 2; D006898:Hydroxylamines; C585287:N-(tert-butyl)hydroxylamine; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D025262:Vacuolar Proton-Translocating ATPases