title: BH3-only protein Bid is dispensable for seizure-induced neuronal death and the associated nuclear accumulation of apoptosis-inducing factor.
abstract: Prolonged seizures activate members of the Bcl-2 homology domain 3-only sub-group of the Bcl-2 protein family, which are essential for initiation of apoptosis signaling. Bid is a potent pro-apoptotic Bcl-2 homology domain 3-only protein, which upon proteolytic activation translocates to mitochondria to promote activation of the Bax/Bak sub-group of the pro-apoptotic Bcl-2 family and thereby contributes to release of apoptogenic molecules, such as cytochrome c and possibly apoptosis-inducing factor (AIF). Bid-deficient mice have been reported to show reduced lesion volumes after ischemia and trauma in vivo but a causal role for Bid in the setting of seizure-induced neuronal death has not been investigated. In this study, we studied Bid activation following status epilepticus in mice and compared hippocampal damage between wild-type and Bid-deficient animals. Full-length Bid was detected in normal mouse hippocampus and the cleaved (activated) p15 fragment of Bid was detected shortly after status epilepticus. Bid-deficient mice underwent equivalent electrographic seizure responses during status epilepticus as wild-type animals. Hippocampal counts of degenerating neurons and surviving neuron-specific nuclear protein-positive cells were not significantly different between wild-type and Bid-deficient mice. Additionally, nuclear translocation of AIF was not reduced in Bid-deficient compared with wild-type animals subjected to status epilepticus. The present study demonstrates that AIF is not dependent on Bid for mitochondrial release and nuclear import in this model and that while Bid is cleaved during seizure-induced neuronal death, it may be functionally redundant or even not essential.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.forename: Aurelien
authors.initials: A
authors.lastname: Caballero-Caballero
authors.forename: Clara K
authors.initials: CK
authors.lastname: Schindler
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D004828:Epilepsies, Partial / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012640:Seizures / Q000473:pathology*; D013226:Status Epilepticus / Q000473:pathology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C107631:Hrk protein, mouse; D008565:Membrane Proteins; D009479:Neuropeptides; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins