Expression of palmitoyl protein thioesterase in neurons

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerati ve disorder in childhood that is caused by mutations in the gene encoding l ysosomal palmitoyl protein thioesterase (PPT). INCL is characterized by mas sive and selective loss of cortical neurons. Here we have analyzed the intr acellular processing and localization of adenovirus-mediated PPT in mouse p rimary neurons and NGF-induced PC-12 cells. The neuronal processing of PPT was found to be similar to that observed in peripheral cells, and a signifi cant amount of the PPT enzyme was secreted in the primary neurons. Immunofl uorescence analysis of the neuronal cells infected with wild-type PPT showe d a granular staining pattern in the cell soma and neuronal shafts. Interes tingly, PPT was also found in the synaptic ends of the neuronal cells and t he staining pattern of the enzyme colocalized to a significant extent with the synaptic markers SV2 and synaptophysin. These in vitro data correspond with the distribution of endogeneous PPT in mouse brain and suggest that PP T may not solely be a lysosomal hydrolase. The specific targeting of PPT in to the neuritic shafts and nerve terminals indicates that PPT may be associ ated with the maintenance of synaptic function. Furthermore, since a substa ntial amount of PPT is secreted by neurons, it is tempting to speculate tha t the enzyme could also have an extracellular substrate. (C) 2000 Academic Press.