A molecular chaperone inducer protects neurons from ER stress

The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins the ER lumen. Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases cerebral ischemia. In a screen for compounds that induce the ER-mediated chaperone BiP (immunoglobulin heavy-chain protein)/GRP78 (78 kDa glucose-regulated protein), we identified BiP inducer X (BIX). BIX preferentially induced BiP with inductions of GRP94 (94 kDa glucose-regulated protein), calreticulin, and C/EBP homologous protein. The induction of mRNA by BIX was mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting it may be a potential therapeutic agent for cerebral diseases caused by ER stress.