Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.

ABSTRACT: Neurodegeneration is a devastating manifestation in most lysosomal storage disorders (LSDs). Loss-of-function mutations in CLN1, 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 Cln1^-/- mice, Ppt1 deficiency misroutes N

SUBMITTER: Appu AP 

PROVIDER: S-EPMC12057685 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature