title: Causal role of apoptosis-inducing factor for neuronal cell death following traumatic brain injury.
abstract: Traumatic brain injury (TBI) consists of two phases: an immediate phase in which damage is caused as a direct result of the mechanical impact; and a late phase of altered biochemical events that results in delayed tissue damage and is therefore amenable to therapeutic treatment. Because the molecular mechanisms of delayed post-traumatic neuronal cell death are still poorly understood, we investigated whether apoptosis-inducing factor (AIF), a pro-apoptotic mitochondrial molecule and the key factor in the caspase-independent, cell death signaling pathway, plays a causal role in neuronal death following TBI. Using an in vitro model of neuronal stretch injury, we demonstrated that AIF translocated from mitochondria to the nucleus of neurons displaying axonal disruption, chromatin condensation, and nuclear pyknosis in a caspase-independent manner, whereas astrocytes remained unaffected. Similar findings were observed following experimental TBI in mice, where AIF translocation to the nucleus coincided with delayed neuronal cell death in both cortical and hippocampal neurons. Down-regulation of AIF in vitro by siRNA significantly reduced stretch-induced neuronal cell death by 67%, a finding corroborated in vivo using AIF-deficient harlequin mutant mice, where secondary contusion expansion was significantly reduced by 44%. Hence, our current findings demonstrate that caspase-independent, AIF-mediated signaling pathways significantly contribute to post-traumatic neuronal cell death and may therefore represent novel therapeutic targets for the treatment of TBI.
authors.affiliation: Department of Biology, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Slemmer
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.forename: Stefan
authors.initials: S
authors.lastname: Landshamer
authors.forename: Raimund
authors.initials: R
authors.lastname: Trabold
authors.forename: Julia
authors.initials: J
authors.lastname: Grohm
authors.forename: Ardavan
authors.initials: A
authors.lastname: Ardeshiri
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Marva I
authors.initials: MI
authors.lastname: Sweeney
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.forename: John T
authors.initials: JT
authors.lastname: Weber
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D055815:Young Adult
chemical_list: D051033:Apoptosis Inducing Factor; D034741:RNA, Small Interfering; D020169:Caspases