Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerati ve storage disorder in children caused by mutations in the palmitoyl protei n thioesterase gene (PPT1). We have investigated here four naturally occurr ing previously described PPT1 mutations and show that all cause severe effe cts on PPT1 enzyme activity in transiently transfected COS-1 cells. Two of the mutations (delPhe84 and insCys45) cause a classical INCL phenotype and two (Thr75Pro and Leu219Gln) result in a late onset disease phenotype. All these mutated PPT1 molecules have severely altered intracellular localizati on in transiently transfected BHK-cells, whereas in mouse primary neuron cu ltures different effects were observed. In neurons the delPhe84 and insCys4 5 mutant polypeptides were targeted to the ER. Interestingly the Thr75Pro a nd Leu219Gln mutations had only minor effects on the neuronal trafficking o f PPT1 and the mutated polypeptides were observed in neuronal shafts and sh owed colocalization with the presynaptic marker SV2. Our data indicates tha t neuronal cells provide an excellent model to study the genotype-phenotype correlation in INCL.