HUMAN PALMITOYL PROTEIN THIOESTERASE - EVIDENCE FOR LYSOSOMAL TARGETING OF THE ENZYME AND DISTURBED CELLULAR ROUTING IN INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS

Palmitoyl protein thioesterase (PPT) is an enzyme that removes palmita te residues from various S-acylated proteins in vitro. We recently ide ntified mutations in the human PPT gene in patients suffering from a n eurodegenerative disease in childhood, infantile neuronal ceroid lipof uscinosis (INCL), with dramatic manifestations limited to the neurons of neocortical origin, Here we have expressed the human PPT cDNA in CO S-1 cells and demonstrate the lysosomal targeting of the enzyme via th e mannose 6-phosphate receptor-mediated pathway. The enzyme was also s ecreted into the growth medium and could be endocytosed by recipient c ells. We further demonstrate the disturbed intracellular routing of PP T carrying the worldwide most common INCL mutation, Arg122Trp, to lyso somes. The results provide evidence that INCL represents a novel lysos omal enzyme deficiency. Further, the defect in the PPT gene causing a neurodegenerative disorder suggests that depalmitoylation of the still uncharacterized substrate(s) for PPT is critical for postnatal develo pment or maintenance of cortical neurons.