title: Endoplasmic reticulum protein BI-1 modulates unfolded protein response signaling and protects against stroke and traumatic brain injury.
abstract: Bax-Inhibitor-1 (BI-1) is an evolutionarily conserved cytoprotective protein that resides in membranes of the endoplasmic reticulum (ER). BI-1's cytoprotective activity is manifested in the context of ER stress, with previous studies showing that BI-1 modulates several ER-associated functions, including Unfolded Protein Response (UPR) signaling. Here we investigated the role of BI-1 in neuroprotection by generating transgenic mice in which BI-1 was constitutively expressed from a neuronal-specific promoter. Cultured primary cortical neurons from BI-1 transgenic mouse embryos exhibited greater resistance to cell death induced by agents known to cause ER stress compared to their non-transgenic counterparts. While brain morphology and vasculature of BI-1 mice appeared to be unchanged from normal non-transgenic mice, BI-1 transgenic mice showed reduced brain lesion volumes and better performance in motoric tests, compared with non-transgenic littermates, in two models of acute brain injury: stroke caused by middle cerebral artery occlusion (MCAO) and traumatic brain injury (TBI) caused by controlled cortical impact. Furthermore, brain tissue from BI-1 transgenic mice showed reduced levels of apoptotic cells and reduced induction of markers of ER stress after brain injury, including CHOP protein expression. In summary, our findings demonstrate that enforced neuronal expression of BI-1 reduces ER stress and provides protection from acute brain injury, suggesting that strategies for enhancing BI-1 expression or activity should be considered for development of new therapies for counteracting the consequences of stroke and acute brain trauma.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd La Jolla, CA 92037, USA.
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Lucy
authors.initials: L
authors.lastname: Xu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xu
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Christina L
authors.initials: CL
authors.lastname: Kress
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Irie
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C490015:Tmbim6 protein, mouse