{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:01:52Z","timestamp":1787313712132,"version":"build-2736575974"},"reference-count":70,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"19","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,5,9]]},"abstract":"<jats:p>\n                    Neurodegeneration is a devastating manifestation in most lysosomal storage disorders (LSDs). Loss-of-function mutations in\n                    <jats:italic toggle=\"yes\">CLN1<\/jats:italic>\n                    , encoding palmitoyl-protein thioesterase-1 (PPT1), cause CLN1 disease, a devastating neurodegenerative LSD that has no curative treatment. Numerous proteins in the brain require dynamic S-palmitoylation (palmitoylation-depalmitoylation) for trafficking to their destination. Although PPT1 depalmitoylates S-palmitoylated proteins and its deficiency causes CLN1 disease, the underlying pathogenic mechanism has remained elusive. We report that Niemann-Pick C1 (NPC1), a polytopic membrane protein mediating lysosomal cholesterol egress, requires dynamic S-palmitoylation for trafficking to the lysosome. In\n                    <jats:italic toggle=\"yes\">\n                      Cln1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, Ppt1 deficiency misroutes NPC1-dysregulating lysosomal cholesterol homeostasis. Along with this defect, increased oxysterol-binding protein (OSBP) promotes cholesterol-mediated activation of mechanistic target of rapamycin C1 (mTORC1), which inhibits autophagy contributing to neurodegeneration. Pharmacological inhibition of OSBP suppresses mTORC1 activation, rescues autophagy, and ameliorates neuropathology in\n                    <jats:italic toggle=\"yes\">\n                      Cln1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Our findings reveal a previously unrecognized role of\n                    <jats:italic toggle=\"yes\">CLN1<\/jats:italic>\n                    \/PPT1 in lysosomal cholesterol homeostasis and suggest that suppression of mTORC1 activation may be beneficial for CLN1 disease.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adr5703","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T13:58:56Z","timestamp":1746626336000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4567-2961","authenticated-orcid":true,"given":"Abhilash P.","family":"Appu","sequence":"first","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine, Eunice 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