The palmitoyl protein thioesterase-2 (PPT2) gene encodes a lysosomal thioesterase homologous to PPT1, which is the enzyme defective in the human disorder called infantile neuronal ceroid lipofuscinosis.
In the present study, new PCR-OLA methods were developed for the detection of the major mutations causing infantile neuronal ceroid lipofuscinosis (INCLFin), congenital nephrotic syndrome of Finnish type (NPHS1 FinMajor and FinMinor) and medium chain acyl-CoA dehydrogenase deficiency (MCAD A985G).
These data indicate neuron-specific changes for F(1)-complex in the Ppt1-deficient cells and give clues for a possible link between lipid metabolism and neurodegeneration in INCL.
We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced.
Results from this study demonstrate quantifiable changes in behavioral functions during progression of murine INCL and suggest that Parkinson-like motor/sensorimotor deficits in Cln1(-/-) mice are not mediated by dopamine deficiency.
Ppt1 function is well conserved from humans to flies; thus the INCL pathologies may be due, in part, to the accumulation of various embryonic neural defects similar to that of Drosophila.
Using the PPT1-knockout (PPT1-KO) mice that mimic INCL, we previously reported that one mechanism of apoptosis involves endoplasmic reticulum (ER) stress-induced caspase-12 activation.
Neuronal death is common to many lysosomal storage diseases but it occurs very early in INCL and we show here that inhibition of PPT1 increases the susceptibility of these cells to apoptotic cell death.
To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 <sup>-/-</sup> ) mice, a model of infantile CLN1 disease.
Palmitoyl-protein thioesterase-2 (PPT2) is a homolog of PPT1, the enzyme that is deficient in the lysosomal storage disorder, infantile neuronal ceroid lipofuscinosis (NCL).
Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons.
We previously reported that oxidative stress-mediated abnormality in mitochondria activates caspases-9 pathway of apoptosis in INCL fibroblasts and in neurons of Ppt1-knockout (Ppt1-KO) mice, which mimic INCL.
To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease).
Although the clinical and pathological features of the GFAP(-/-)Vimentin(-/-)PPT1(-/-) mice are similar to INCL, the disease appears earlier and progresses more rapidly.
Infantile neuronal ceroid lipofuscinosis (INCL) has the earliest onset ( approximately 1.5 years of age) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1).
Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the <i>Ppt1</i> knockout mice and patients with CLN1 disease.
Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs.
Although the clinical and pathological features of the GFAP(-/-)Vimentin(-/-)PPT1(-/-) mice are similar to INCL, the disease appears earlier and progresses more rapidly.
These data provide new insights into the metabolism of PPT1-deficient cells and offer a basis for further studies on cellular processes causing neuronal death in INCL and other neurodegenerative diseases.
Early intervention with cellular transplants of hCNS-SCns into the brains of INCL patients may supply a continuous and long-lasting source of the missingPPT1 and provide some therapeutic benefit through protection of endogenous neurons.
The palmitoyl protein thioesterase-2 (PPT2) gene encodes a lysosomal thioesterase homologous to PPT1, which is the enzyme defective in the human disorder called infantile neuronal ceroid lipofuscinosis.