Caspase-3 cleavage and nuclear localization of caspase-activated DNase in human temporal lobe epilepsy

Programmed cell death (apoptosis) signaling pathways have been implicated in seizure-induced neuronal death and the pathogenesis of human temporal lobe epilepsy (TLE). End-stage DNA fragmentation during cell death may be mediated by nucleases including caspase-activated DNase (CAD), apoptosis-induci...

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Published in:Journal of cerebral blood flow and metabolism 2006-04, Vol.26 (4), p.583-589
Main Authors: Schindler, Clara K, Pearson, Erik G, Bonner, Helena P, So, Norman K, Simon, Roger P, Prehn, Jochen HM, Henshall, David C
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis Inducing Factor - analysis
Biological and medical sciences
Caspase 3
Caspases - analysis
Caspases - metabolism
Cell Fractionation
Cell Nucleus - enzymology
Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges
Deoxyribonucleases - metabolism
Endodeoxyribonucleases - analysis
Epilepsy, Temporal Lobe
Fundamental and applied biological sciences. Psychology
Hippocampus
Humans
Medical sciences
Metabolic diseases
Neurology
Other metabolic disorders
Pigments (porphyrias, hyperbilirubinemias...)
Signal Transduction
Vascular diseases and vascular malformations of the nervous system
Vertebrates: nervous system and sense organs
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Summary:Programmed cell death (apoptosis) signaling pathways have been implicated in seizure-induced neuronal death and the pathogenesis of human temporal lobe epilepsy (TLE). End-stage DNA fragmentation during cell death may be mediated by nucleases including caspase-activated DNase (CAD), apoptosis-inducing factor (AIF) and endonuclease G. In the present study, we investigated the subcellular localization of these nucleases in resected hippocampus from TLE patients and autopsy controls. Subcellular fractionation determined levels of CAD were significantly higher in the nuclear fraction of TLE samples compared with controls, and semiquantitative immunohistochemistry revealed cleaved caspase-3 positive cells in TLE sections but not controls. While mitochondrial levels of AIF and endonuclease G were higher in TLE samples than controls, nuclear localization of AIF was limited and restricted to cells that were negative for cleaved caspase-3. Nuclear accumulation of endonuclease G was not found in TLE samples. These data support ongoing caspase-dependent apoptosis signaling in human TLE and suggest that interventions targeting such pathways may have potential as adjunctive neuroprotective therapy in epilepsy.
ISSN:0271-678X
1559-7016
DOI:10.1038/sj.jcbfm.9600219