Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis
T. Salonen et al., Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis, MOL CELL NE, 18(2), 2001, pp. 131-140
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.