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Dynamic S\u2010palmitoylation (palmitoylation\u2010depalmitoylation), like phosphorylation\u2010dephosphorylation, regulates the function of numerous proteins, especially in the brain. While a family of 23 palmitoyl\u2010acyl transferases (PATS), commonly known as ZDHHCs, catalyze S\u2010palmitoylation of proteins, the thioesterases, localized either in the cytoplasm (eg, APT1) or in the lysosome (eg, PPT1) mediate depalmitoylation. Previously, we reported that APT1 requires dynamic S\u2010palmitoylation for shuttling between the cytosol and the plasma membrane. APT1 depalmitoylated H\u2010Ras to regulate its signaling pathway that stimulates cell proliferation. Although we demonstrated that APT1 catalyzed its own depalmitoylation, the ZDHHC(s) that S\u2010palmitoylated APT1 had remained unidentified. We report here that ZDHHC5 and ZDHHC23 catalyze APT1 S\u2010palmitoylation. Intriguingly, lysosomal Ppt1\u2010deficiency in <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse, a reliable animal model of INCL, markedly reduced ZDHHC5 and ZDHHC23 levels. Remarkably, in the brain of these mice decreased ZDHHC5 and ZDHHC23 levels suppressed membrane\u2010bound APT1, thereby, increasing plasma membrane\u2010localized H\u2010Ras, which activated its signaling pathway stimulating microglia proliferation. Increased inflammatory cytokines produced by microglia together with increased complement C1q level contributed to the transformation of astrocytes to neurotoxic A1 phenotype. Importantly, neuroinflammation was ameliorated by treatment of <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice with a PPT1\u2010mimetic small molecule, N\u2010tert(Butyl)hydroxylamine (NtBuHA). Our results revealed a novel pathway to neuropathology in an INCL mouse model and uncovered a previously unrecognized mechanism of the neuroprotective actions of NtBuHA and its potential as a drug target.<\/jats:p>","DOI":"10.1002\/jimd.12379","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T14:08:19Z","timestamp":1616162899000},"page":"1051-1069","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["In a mouse model of <scp>INCL<\/scp> reduced S\u2010palmitoylation of cytosolic thioesterase <scp>APT1<\/scp> contributes to microglia proliferation and neuroinflammation"],"prefix":"10.1002","volume":"44","author":[{"given":"Tamal","family":"Sadhukhan","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 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