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Deletion of Atf6α enhances kainate-induced neuronal death in mice
Dai Kezuka1, Mika Tkarada-Iemata1, Tsuyoshi Hattori1
1Department of Neuroanatomy, Graduate School of Medical Science, Kanazawa University, Japan.
Abstract:
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 6α (ATF6α), 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 Atf6α(-/-) mice revealed that KA induced pronounced neuronal death in the CA3 region of Atf6α(-/-) mice. The enhanced neuronal death in Atf6α(-/-) 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 Atf6α(-/-) mice after KA injection. Our results suggest that ATF6α plays an important role in neuronal survival after KA-induced excitotoxicity through the regulation of Ca(2+) response and neuronal activity.
Insights
Activating transcription factor 6-alpha (ATF6α) protects neurons from excitotoxicity by regulating calcium response. Deleting ATF6α worsens neuronal death in epilepsy and stroke models, highlighting its crucial survival role.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- Excessive L-glutamate causes neuronal damage in epilepsy and stroke.
- The 150-kDa oxygen-regulated protein (ORP150) mitigates L-glutamate-induced neuronal death by enhancing ER Ca(2+) homeostasis.
- Activating transcription factor 6-alpha (ATF6α) is a key transcriptional regulator of the endoplasmic reticulum (ER).
Purpose of the Study:
- To investigate the role of ATF6α in neuronal survival following excitotoxicity using a mouse model.
- To elucidate the mechanisms by which ATF6α influences neuronal response to L-glutamate-induced injury.
Main Methods:
- Intrahippocampal kainic acid (KA) injection in wild-type (WT) and Atf6α(-/-) mice.
- Analysis of neuronal death, molecular chaperone expression (GRP78), and c-fos induction.
- Treatment with dantrolene, a ryanodine receptor inhibitor.
Main Results:
- KA injection increased Hspa5 (encoding GRP78) expression in WT mice.
- Atf6α(-/-) mice exhibited significantly increased neuronal death in the CA3 region post-KA.
- Neuronal death in Atf6α(-/-) mice correlated with reduced ER chaperones and increased c-fos.
- Dantrolene partially rescued KA-induced neuronal death in Atf6α(-/-) mice.
Conclusions:
- ATF6α is crucial for neuronal survival against KA-induced excitotoxicity.
- ATF6α regulates neuronal Ca(2+) response and activity, contributing to neuroprotection.
- Targeting ATF6α pathways may offer therapeutic strategies for stroke and epilepsy.
