| First Author | Kezuka D | Year | 2016 |
| Journal | Neurochem Int | Volume | 92 |
| Pages | 67-74 | PubMed ID | 26724566 |
| Mgi Jnum | J:321031 | Mgi Id | MGI:6838674 |
| Doi | 10.1016/j.neuint.2015.12.009 | Citation | Kezuka D, et al. (2016) Deletion of Atf6alpha enhances kainate-induced neuronal death in mice. Neurochem Int 92:67-74 |
| abstractText | Excessive amount of L-glutamate in the brain causes neuronal damage in various pathological conditions including epilepsy and stroke. We previously reported that the 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone in the endoplasmic reticulum (ER), inhibited the L-glutamate-induced neuronal death, at least partly, by improving Ca(2+) homeostasis in the ER. In the present study, we analyzed the role of activating transcription factor 6alpha (ATF6alpha), an upstream transcriptional factor critical for the operation of the ER, using mouse intrahippocampal kainate (KA) injection model. Expression of Hspa5, which encodes the molecular chaperone 78 kDa glucose-regulated protein (GRP78), increased after KA injection in the wild type (WT) mice. Comparative analysis using WT and Atf6alpha(-/-) mice revealed that KA induced pronounced neuronal death in the CA3 region of Atf6alpha(-/-) mice. The enhanced neuronal death in Atf6alpha(-/-) mice was associated with reduced expression of molecular chaperones in the ER and significant induction of c-fos in the hippocampal neurons. Furthermore, an injection of dantrolene, an inhibitor of ryanodine receptor, partially rescued these effects in Atf6alpha(-/-) mice after KA injection. Our results suggest that ATF6alpha plays an important role in neuronal survival after KA-induced excitotoxicity through the regulation of Ca(2+) response and neuronal activity. |
