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.

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

“…Similar to contusion analyses in Bcl-2 overexpressing mice, cortical contusion size in constitutively BI-1 overexpressing mice was reduced at 2 h to 2 weeks after injury compared to wild-type mice (Fig. 2a) [54]. Here, however, cortical neuroprotection was associated with decreased posttraumatic apoptosis, as detected by TUNEL staining at 6 and 24 h (Fig.…”

“…BI-1 transgenic mice, however, demonstrated better wire grip performance at 7 days post-CCI, whereas their wild-type counterparts showed sustained deficits (Fig. 2c) [54]. Based on these transgenic mouse studies, increased expression of Bcl-2 and BI-1 is sufficient to reduce injury-induced cortical contusion size, presumably through suppression of apoptosis.…”

“…Each experimental animal is plotted, in addition to the mean ± standard error (p<0.001). Modified from Krajewska et al [54] and reproduced with permission from Elsevier performance were observed with Bcl-2 overexpression at several days past the injury [52,53], and only select motor improvement was seen in transgenic mice with the inclined plane test [51]. BI-1 transgenic mice, however, demonstrated better wire grip performance at 7 days post-CCI, whereas their wild-type counterparts showed sustained deficits (Fig.…”

“…Here, however, cortical neuroprotection was associated with decreased posttraumatic apoptosis, as detected by TUNEL staining at 6 and 24 h (Fig. 2b) and an early reduction in markers of endoplasmic reticulum stress, including CCAAT/-enhancerbinding protein homologous protein (CHOP), phosphoJun, and c-Jun [54]. A cellular balance in favor of the antiapoptotic proteins Bcl-2 and BI-1 appears to promote a neuroprotective outcome at both acute and long-term time points.…”

Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

“…Reduced ER stress responses have been suggested to allow for protection against ER stress by BI-1 (14,16,17). However, the ER stress response occurs as an adaptation of signal transduction rather than a direct mediator for cell damage or death (1,2,18).…”