Heinonen_2000_Mol.Genet.Metab_69_123

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder in childhood that is caused by mutations in the gene encoding lysosomal palmitoyl protein thioesterase (PPT). INCL is characterized by massive and selective loss of cortical neurons. Here we have analyzed the intracellular processing and localization of adenovirus-mediated PPT in mouse primary 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 significant amount of the PPT enzyme was secreted in the primary neurons. Immunofluorescence analysis of the neuronal cells infected with wild-type PPT showed a granular staining pattern in the cell soma and neuronal shafts. Interestingly, PPT was also found in the synaptic ends of the neuronal cells and the 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 PPT may not solely be a lysosomal hydrolase. The specific targeting of PPT into the neuritic shafts and nerve terminals indicates that PPT may be associated with the maintenance of synaptic function. Furthermore, since a substantial amount of PPT is secreted by neurons, it is tempting to speculate that the enzyme could also have an extracellular substrate.