Distinct nuclear and cytoplasmic localization of caspase cleavage products in two models of induced apoptotic death in dopamine neurons of the substantia nigra.
An emerging theme in programmed cell death (PCD) of neurons is that the mechanisms involved depend on the cellular context and the death-inducing stimulus. One particular class of neurons for which it is important to identify the mechanisms of PCD are the dopamine neurons of the substantia nigra, the neurons which degenerate in Parkinson's disease. PCD has been shown to occur in these neurons during normal development and to be induced in neurotoxin models of parkinsonism. Conventional histologic stains and TUNEL labeling have not revealed morphologic differences in the apoptosis observed in these neurons in any context. We now show that in two models of induced PCD in postmitotic dopamine neurons, one induced by early striatal target injury and another induced by the neurotoxin 6-hydroxydopamine (6OHDA), there are differences in the cellular localization and type of caspase cleavage products. Using two antibodies to caspase cleavage products (fractin and AB127), we show that in the target lesion model immunostaining is localized to the nucleus, whereas in the 6OHDA model intense cytoplasmic as well as nuclear staining is observed. Another antibody, AB246, to a caspase cleavage product of spectrin, immunostains apoptotic profiles only in the 6OHDA model. These findings suggest that the cellular compartment and therefore the role of the caspases may differ in apoptosis induced in pathologic settings, such as that due to neurotoxins, from that observed in models of natural or induced natural cell death. It will be important to recognize these differences in the consideration of caspase inhibitors in the treatment of degenerative neurologic disease.
Oo
Tinmarla F
TF
Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Siman
Robert
R
Burke
Robert E
RE
D000199:Actins / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D009447:Neuroblastoma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis / Q000096:biosynthesis*; D017378:Quinolinic Acid; D051381:Rats; D013049:Spectrin / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
D000199:Actins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D013049:Spectrin; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D020169:Caspases; D017378:Quinolinic Acid; D004298:Dopamine