Dna fragmentation factor 45 mutant mice exhibit resistance to kainic acid-induced neuronal cell death.
Excitotoxicity is a process where glutamate or other excitatory amino acids induce neuronal cell death. Emerging evidence suggests that apoptosis plays a key part in excitotoxic neurodegeneration. The DNA fragmentation factor 45 (DFF45 or ICAD) is a subunit of a heterodimeric DNase complex crucial for DNA fragmentation during apoptosis. Using a DFF45 mutant mouse model, we previously found that DFF45 deficient cells are more resistant to apoptosis than normal control cells. To investigate whether the lack of DFF45 may attenuate neuronal cell death induced by excitotoxicity, we compared kainic acid-induced seizure behavior and neuronal cell death in DFF45 mutant and wild-type control mice. We found that the mutant mice exhibit similar kainic acid-induced seizure severity compared to control mice. However, DFF45 mutant mice are more resistant than control mice to kainic acid-induced CA3 neuronal cell death. Interestingly, residual DNA degradation can be detected in the hippocampus of DFF45 mutant mice that exhibit KA-induced lesions. Our results suggest that a lack of DFF45 can lead to neuronal resistance to excessive activity-induced toxicity.
Zhang
J
J
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.
Lee
H
H
Agarwala
A
A
Wen Lou
D
D
Xu
M
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D017781:Genes, Immediate-Early / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid; D046911:Macromolecular Substances; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
D051017:Apoptosis Regulatory Proteins; D046911:Macromolecular Substances; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C109664:caspase-activated DNase inhibitor; D007608:Kainic Acid