Palmitoyl-protein thioesterase 1

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal thioesterase that catalyzes the removal of palmitoyl fatty acid modifications from proteins and small-molecule thioesters with 14–18 carbon chains (UniProt: P50897). Unlike its homolog PPT2, PPT1 can depalmitoylate both proteins and free palmitoylcysteine, functioning as a critical regulator of protein lipidation homeostasis. Mutations in PPT1 cause ceroid lipofuscinosis, neuronal, type 1 (CLN1), a lysosomal storage disease featuring accumulation of autofluorescent lipopigments and progressive neurodegeneration with seizures, dementia, and visual loss.

PPT1 is primarily a lysosomal protein involved in lipid catabolism and protein post-translational modification turnover (UniProt: P50897). The CLN1 pathology underscores its essential role in maintaining neuronal cellular homeostasis and clearance of lipid-modified protein cargo.

In Alzheimer's disease, PPT1 is significantly upregulated in post-mortem AD brain tissue relative to age-matched controls (mean log2 fold-change: 0.1991; Chaparral AD proteomics). This elevation was detected across quantitative proteomics analysis of subcellular fractions, suggesting a potential compensatory response or dysregulation of palmitoylation metabolism in AD neurodegeneration.