PPT1

Palmitoyl protein thioesterase 1 (PPT1) is a lysosomal depalmitoylating enzyme that removes thioester-linked fatty acids, predominantly palmitate, from S-palmitoylated proteins and thereby promotes the degradation and turnover of lipid-modified proteins during lysosomal catabolism^[1][2]. PPT1 functions within the broader protein depalmitoylation network and contributes to cellular processes associated with lysosomal degradation, autophagy-lysosome function, endocytosis, neuronal morphogenesis, and synaptic maintenance^[3][4][5]. Mechanistically, loss of PPT1 activity impairs the clearance of palmitoylated proteins, leading to intracellular accumulation of ceroid lipofuscin and disruption of lysosomal homeostasis^[4][6]. Mutations in PPT1 cause neuronal ceroid lipofuscinosis type 1 (CLN1), also known as infantile neuronal ceroid lipofuscinosis, a severe neurodegenerative lysosomal storage disorder characterized by progressive neuronal dysfunction and degeneration^[4][6][7]. Experimental studies using PPT1-deficient cells and mouse models have demonstrated defects in endocytosis, synaptic vesicle recycling, neuronal survival, and regional brain integrity, supporting the utility of these models for investigating disease mechanisms and therapeutic strategies^[5][8][7][9]. Compared with the closely related lysosomal thioesterase PPT2, PPT1 uniquely hydrolyzes palmitoylated proteins and palmitoylcysteine substrates, providing a key biochemical distinction that underlies its specialized role in protein depalmitoylation and neurobiology^[10]. For experimental applications, PPT1 has also emerged as a pharmacological target in lysosome-centered studies, and inhibition of PPT1 has been used to investigate lysosomal signaling, autophagy regulation, and disease-associated cellular pathways^[11].