Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice

PPT1 and PPT2 encode two lysosomal thioesterases that catalyze the hydrolys is of long chain fatty acyl CoAs. In addition to this function, PPT1 (palmi toyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome. PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neurona l ceroid lipofuscinosis (also known as infantile Batten disease). in the cu rrent work, we engineered disruptions in the PPT1 and PPT2 genes to create "knockout" mice that were deficient in either enzyme. Both lines of mice we re viable and fertile. However, both lines developed spasticity (a "claspin g" phenotype) at a median age of 21 wk and 29 wk, respectively. Motor abnor malities progressed in the PPT1 knockout mice, leading to death by 10 mo of age. In contrast, the majority of PPT2 mice were alive at 12 mo. Myoclonic jerking and seizures were prominent in the PPT1 mice. Autofluorescent stor age material was striking throughout the brains of both strains of mice. Ne uronal loss and apoptosis were particularly prominent in PPT1-deficient bra ins. These studies provide a mouse model for infantile neuronal ceroid lipo fuscinosis and further suggest that PPT2 serves a role in the brain that is not carried out by PPT1.