title: Cell death pathways in juvenile Batten disease.
abstract: Apoptosis, Golgi fragmentation and elevated ceramide levels occur in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) neurons, lymphoblasts and fibroblasts. Our purpose was to examine whether apoptosis is the mechanism of cell death in JNCL. This was tested by analyzing caspase-dependent/independent pathways and autophagy, and caspase effects on ceramide and Golgi fragmentation. zVAD prevented caspase activation, but not all cell death. Inhibiting caspase-8 suppressed caspases more than inhibition of any other caspase. Inhibiting caspase-8/6 was synergistic. zVAD suppressed autophagy. 3-methyladenine suppressed caspase activation less than zVAD did. Blocking autophagy/caspase-8/or-6 was synergistic. Blocking autophagy/caspase-3/or-9 was not. Inhibiting caspase-9/3 suppressed autophagy. Golgi fragmentation was suppressed by zVAD, and blocked by CLN3. CLN3, not zVAD, prevented ceramide elevation.
  
  
  CONCLUSIONS
  caspase-dependent/independent apoptosis and autophagy occur caspase-dependent pathways initiate autophagy Golgi fragmentation results from apoptosis ceramide elevation is independent of caspases, and CLN3 blocks all cell death, prevents Golgi fragmentation and elevation of ceramide in JNCL.
authors.affiliation: Departments of Pediatrics and Neurobiology, Duke University Medical Center, MSRB, Research Drive, Box 2604, Durham, NC 27710, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Persaud-Sawin
authors.forename: R-M N
authors.initials: RM
authors.lastname: Boustany
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D006056:Golgi Apparatus / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology / Q000503:physiopathology*; D013109:Sphingomyelins / Q000378:metabolism; D014162:Transfection
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C105199:CLN3 protein, human; D061945:Caspase Inhibitors; D002518:Ceramides; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D013109:Sphingomyelins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D005047:Etoposide; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases