title: Apoptosis in caspase-inhibited neurons.
abstract: BACKGROUND
  There is growing evidence of apoptosis in neurodegenerative disease. However, it is still unclear whether the pathological manifestations observed in slow neurodegenerative diseases are due to neuronal loss or whether they are related to independent degenerative events in the axodendritic network. It also remains elusive whether a single, caspase-based executing system involving caspases is responsible for neuronal loss by apoptosis.
  
  
  METHODS
  Long-term exposure to the microtubule-disassembling agent, colchicine, was used to disrupt the axodendritic network and eventually trigger caspase-3-mediated apoptosis in cultures of cerebellar granule cells. For this model, we investigated the role of Bcl-2 and caspases in neurite degeneration and death of neuronal somata.
  
  
  RESULTS
  Early degeneration of the axodendritic network occurred by a Bcl-2 and caspase-independent mechanism. Conversely, apoptosis of the cell body was delayed by Bcl-2 and initially blocked by caspase inhibition. However, when caspase activity was entirely blocked by zVAD-fmk, colchicine-exposed neurons still underwent delayed cell death characterized by cytochrome c release, chromatin condensation to irregularly shaped clumps, DNA-fragmentation, and exposure of phosphatidylserine. Inhibitors of the proteasome reduced these caspase-independent apoptotic-like features of the neuronal soma.
  
  
  CONCLUSIONS
  Our data suggest that Bcl-2-dependent and caspase-mediated death programs account only partially for neurodegenerative changes in injured neurons. Blockage of the caspase execution machinery may only temporarily rescue damaged neurons and classical apoptotic features can still appear in caspase-inhibited neurons.
authors.affiliation: Department of Biology, University of Konstanz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Volbracht
authors.forename: M
authors.initials: M
authors.lastname: Leist
authors.forename: S A
authors.initials: SA
authors.lastname: Kolb
authors.forename: P
authors.initials: P
authors.lastname: Nicotera
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001692:Biological Transport; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D003078:Colchicine / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D010718:Phosphatidylserines / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D002843:Chromatin; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D007976:Leupeptins; D009097:Multienzyme Complexes; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D003078:Colchicine