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bioRxiv · 10.1101/2021.02.01.429116

The ATF6β-calreticulin axis protects hippocampal neurons against endoplasmic reticulum stress and excitotoxicity

Nguyen, D. T.·Le, T. M.·Hattori, T.·Takarada-Iemata, M.·Ishii, H.·Roboon, J.·Tamatani, T.·Kannon, T.·Hosomichi, K.·Tajima, A.·Taniuchi, S.·Miyake, M.·Oyadomari, S.·Saito, S.·Mori, K.·Hori, O.
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Abstract

While ATF6 plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6{beta} is largely unknown. Here, we demonstrate that ATF6{beta} is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca2+-binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system of Atf6b-/- mice, and restored by ATF6{beta}. Analysis using cultured hippocampal neurons revealed that ATF6{beta} deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6{beta}, calreticulin, Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in hippocampi of Atf6b-/- and Calr+/- mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6{beta}-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+ homeostasis under ER stress.

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Nguyen, D. T., Le, T. M., Hattori, T., Takarada-Iemata, M., Ishii, H., Roboon, J., Tamatani, T., Kannon, T., Hosomichi, K., Tajima, A., Taniuchi, S., Miyake, M., Oyadomari, S., Saito, S., Mori, K., Hori, O.. 2021-02-02. The ATF6β-calreticulin axis protects hippocampal neurons against endoplasmic reticulum stress and excitotoxicity. https://doi.org/10.1101/2021.02.01.429116

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