National Academy of Sciences, Proceedings of the National Academy of Sciences, 13(118), 2021
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Significance This study reports that the intermediate filament protein GFAP is modified with protein palmitoylation. Increased GFAP expression and palmitoylation is involved in astrocyte proliferation and astrogliosis. We demonstrate that GFAP palmitoylation is regulated by PPT1, a palmitoylprotein thioesterase linked to a childhood neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis. A palmitoylation-defective mutant of GFAP attenuates astrogliosis and the concurrent pathology in a loss-of-function PPT1 mouse. We conclude that accumulation of palmitoylated GFAP contributes to the pathogenesis of astrogliosis and neurodegeneration, suggesting that targeting the modified cysteine in GFAP may be a potential therapeutic strategy for the treatment of infantile neuronal ceroid lipofuscinosis and other neurodegenerative disorders.