Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The infantile neuronal ceroid lipofuscinosis (INCL), a rare (one in 100 000 births) but one of the most lethal inherited neurodegenerative storage disorders of childhood, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in s-acylated (palmitoylated) proteins and facilitates their degradation and/or recycling. Thus, PPT1-deficiency leads to an abnormal intracellular accumulation of s-acylated proteins causing INCL pathogenesis. Although neuronal apoptosis is the suggested cause of neurodegeneration in this disease, the molecular mechanism(s) remains poorly understood. We recently reported that one of the major pathways of neuronal apoptosis in PPT1-knockout (PPT1-KO) mice that mimic INCL, is mediated by endoplasmic reticulum (ER) stress-induced caspase-12 activation. ER stress also increases the production of reactive oxygen species (ROS), disrupts Ca(2+) homeostasis and increases the potential for destabilizing mitochondrial membrane. Mitochondrial membrane destabilization activates caspase-9 present in this organelle, and can mediate apoptosis. We report here that the levels of superoxide dismutase (SOD), most likely induced by ROS, in human INCL as well as PPT1-KO mouse brain tissues are markedly elevated. Moreover, we demonstrate that activated caspase-3 and cleaved-PARP, indicative of apoptosis, are also increased in these tissues. Using cultured neurospheres from PPT1-KO and wild-type mouse fetuses, we further demonstrate that the levels of ROS, SOD-2, cleaved-caspase-9, activated caspase-3 and cleaved-PARP are elevated. We propose that: (i) ER stress due to PPT1-deficiency increases ROS and disrupts calcium homeostasis activating caspase-9 and (ii) caspase-9 activation mediates caspase-3 activation and apoptosis contributing to rapid neurodegeneration in INCL.
 ...
PMID:Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. 1657

Infantile neuronal ceroid lipofuscinosis (INCL), a neurodegenerative storage disorder of childhood, is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in S-acylated (palmitoylated) proteins and its mutation causes abnormal intracellular accumulation of fatty-acylated proteins and peptides leading to INCL pathogenesis. Although apoptosis is the suggested cause of neurodegeneration in INCL, the molecular mechanism(s) of apoptosis remains unclear. 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. However, the human caspase-12 gene contains several mutations, which make it functionally inactive. Thus, it has been suggested that human caspase-4 is the counterpart of murine caspase-12. Here we report that in the human INCL brain ER stress-induced activation of unfolded protein response (UPR) mediates caspase-4 and caspase-3 activation and apoptosis. Moreover, we show that the INCL brain contains high level of growth-associated protein-43 (GAP-43), which is known to undergo palmitoylation. We also demonstrate that transfection of cultured INCL cells with a green fluorescent protein-GAP-43 cDNA construct shows abnormal localization of this protein in the ER. Further, INCL cells manifest evidence of ER stress and UPR (elevated levels of Grp-78/Bip and GADD153), caspase-4 as well as caspase-3 activation and cleavage of poly(ADP)-ribose polymerase, a compelling sign of apoptosis. Most importantly, we show that inhibition of caspase-4 activity protects INCL cells from undergoing apoptosis. Our results provide insight into at least one of the molecular mechanisms of apoptosis in INCL and may allow the identification of potential targets for therapeutic intervention.
 ...
PMID:Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL. 1664 70