Deletion of Atf6α enhances kainate-induced neuronal death in mice

Kezuka, Dai; Tkarada-Iemata, Mika; Hattori, Tsuyoshi; Mori, Kazutoshi; Takahashi, Ryōsuke; Kitao, Yasuko; Hori, Osamu

doi:10.1016/j.neuint.2015.12.009

Cited by 18 publications

(18 citation statements)

References 27 publications

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“…; Kezuka et al . ). To determine the activation status of ATF6α in EAE lesions, we performed immunohistochemistry for KDEL (Fig.…”

Section: Resultsmentioning

confidence: 97%

Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis

Ishii

et al. 2016

Journal of Neurochemistry

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Accumulating evidence suggests a critical role for the unfolded protein response in multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the relevance of activating transcription factor 6α (ATF6α), an upstream regulator of part of the unfolded protein response, in EAE. The expressions of ATF6α‐target molecular chaperones such as glucose‐regulated protein 78 (GRP78) and glucose‐regulated protein 94 (GRP94) were enhanced in the acute inflammatory phase after induction of EAE. Deletion of Atf6α suppressed the accumulation of T cells and microglia/macrophages in the spinal cord, and ameliorated the clinical course and demyelination after EAE induction. In contrast to the phenotypes in the spinal cord, activation status of T cells in the peripheral tissues or in the culture system was not different between two genotypes. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+ T cells to recipient mice (passive EAE) also revealed that CNS‐resident cells are responsible for the phenotypes observed in Atf6α−/− mice. Further experiments with cultured cells indicated that inflammatory response was reduced in Atf6α−/− microglia, but not in Atf6α−/− astrocytes, and was associated with proteasome‐dependent degradation of NF‐κB p65. Thus, our results demonstrate a novel role for ATF6α in microglia‐mediated CNS inflammation. We investigated the relevance of ATF6α, an upstream regulator of part of the UPR, in EAE. Deletion of Atf6α suppressed inflammation, and ameliorated demyelination after EAE. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+ T cells revealed that CNS‐resident cells are responsible for the phenotypes in Atf6α−/− mice. Furthermore, inflammatory response was reduced in Atf6α−/− microglia, and was associated with degradation of NF‐κB p65. Our results demonstrate a novel role for ATF6α in microglia‐mediated inflammation. Cover image for this issue: doi: .

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“…; Kezuka et al . ). To determine the activation status of ATF6α in EAE lesions, we performed immunohistochemistry for KDEL (Fig.…”

Section: Resultsmentioning

confidence: 97%

Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis

Ishii

et al. 2016

Journal of Neurochemistry

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“…ATF6 contributes to iPLA2γ-mediated cytoprotection [ 50 ] Brain Short-form ATF6 KI in forebrain neurons of mice (tamoxifen-inducible activation) Experimental model of stroke induced by middle cerebral artery occlusion Forced activation of ATF6 reduced infarct volume and improved functional outcome following 24 h post-model induction [ 51 ] R6/2 mouse model of Huntington’s disease Derepression of ATF6 was associated with early neuroprotection in this model of Huntington’s disease [ 52 ] Kainate-induced neurotoxicity in hippocampi of mice ATF6α KO Kainate induced pronounced neuronal death in hippocampal CA3 region of ATF6α-KO mice. Hence, ATF6α protects against kainate-induced neurotoxicity in mice [ 53 ] Pancreas/Liver Diet-induced obese mice KOt of ATF6α ATF6α protects pancreatic β-cells from endoplasmic reticulum stress [ 55 ] Zebrafish model of endoplasmic reticulum stress and fatty liver disease Depletion of active ATF6 through mutation in site-1 protease gene ( mbtps1 ) or atf6 morpholino injection ATF6 protects against hepatic steatosis following tunicamycin-induced acute endoplasmic reticulum stress [ 57 ] Pathological Role of ATF6 Signalling Liver OE of activated form of ATF6α in human hepatocellular carcinoma cell line (HLF) ATF6α maylead to hepatocarcinogenesis by directly and indirectly regulating a broad range of genes associated with transformation [ 46 ] Zebrafish model of endoplasmic reticulum stress and fatty liver disease; Depletion of active ATF6 through mutation in site-1 protease gene ( mbtps1 ) or atf6 morpholino injection ATF6 ➔ hepatic steatosis resulting from chronic endoplasmic reticulum stress [ 57 ] Squamous Epithelium Quiescent human squamous carcinoma cells (D-HEp3 cells) KD of ATF6α expression in D-Hep3 cells using chick chorioallantoic membrane and nude mice for xenograft studies ATF6α ➔ dormant cell survival, adaptation of dormant cells to chemotherapy, nutritional stress and the in vivo microenvironment ATF6α-Rheb-mTOR signalling ➔ survival and adaptation of carcinoma cells [ 47 ] Pancreas Diet-induced obe...…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, conditional and tamoxifen-induced forced activation of ATF6 in forebrain neurons reduced infarct volume and improved functional recovery in a mouse model of stroke [ 51 ]. Moreover, the ATF6 branch of the UPR is associated with hippocampal and striatal neuroprotection in models of Huntington’s disease and neurotoxicity, respectively [ 52 , 53 ]. In addition, small molecule ATF6 activation corrects proteostatic imbalances and attenuates inappropriate secretion and aggregation of, for instance, amyloidogenic proteins in disorders such as systemic amyloidosis which affects various organ systems [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

A lifetime of stress: ATF6 in development and homeostasis

2018

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BackgroundActivating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER)-localised protein and member of the leucine zipper family of transcription factors. Best known for its role in transducing signals linked to stress to the endoplasmic reticulum, the 50 kDa activated form of ATF6 is now emerging as a major regulator of organogenesis and tissue homeostasis. Responsible for the correct folding, secretion and membrane insertion of a third of the proteome in eukaryotic cells, the ER encompasses a dynamic, labyrinthine network of regulators, chaperones, foldases and cofactors. Such structures are crucial to the extensive protein synthesis required to undergo normal development and maintenance of tissue homeostasis. When an additional protein synthesis burden is placed on the ER, ATF6, in tandem with ER stress transducers inositol requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), slows the pace of protein translation and induces the production of stress-reducing chaperones and foldases.Main TextIn the context of development and tissue homeostasis, however, distinct cellular impacts have been attributed to ATF6. Drawing on data published from human, rodent, fish, goat and bovine research, this review first focuses on ATF6-mediated regulation of osteo- and chondrogenesis, ocular development as well as neuro- and myelinogenesis. The purported role of ATF6 in development of the muscular and reproductive systems as well as adipo- and lipogenesis is then described. With relevance to cardiac disease, cancer and brain disorders, the importance of ATF6 in maintaining tissue homeostasis is the subject of the final section.ConclusionIn conclusion, the review encourages further elucidation of ATF6 regulatory operations during organogenesis and tissue homeostasis, to spawn the development of ATF6-targeted therapeutic strategies.

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“…Kainate (KA), an agonist of glutamate receptors, causes Ca 2+ -dependent hyperactivation of neurons, followed by the induction of ER stress and neuronal death in the hippocampus (Kezuka et al , 2016). We and other groups have demonstrated the protective role of UPR signaling in KA-injected mice (Kitao et al , 2001; Sokka et al , 2007; Kezuka et al , 2016). In this study, we investigated the role of ATF6β-CRT axis and expression of its components in these mice.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that ATF6α contributes to both neuronal survival and glial activation in different neuropathological situations. Deletion of Atf6α or that of a downstream molecular chaperone, Hyou1 , sensitizes hippocampal neurons to glutamate-induced toxicity most likely via Ca 2+ overload and neuronal hyperactivity in vivo (Kitao et al , 2001; Kezuka et al , 2016). Atf6α deficiency is also associated with reduced astroglial activation and glial scar formation in mouse models of Parkinson’s disease (Hashida et al , 2012) and stroke (Yoshikawa et al , 2015), respectively, both of which are associated with an enhanced level of neuronal death.…”

Section: Introductionmentioning

confidence: 99%

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

Nguyen

Hattori

et al. 2021

Preprint

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While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β 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 ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, 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 ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+ homeostasis under ER stress.

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Deletion of Atf6α enhances kainate-induced neuronal death in mice

Cited by 18 publications

References 27 publications

Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis

Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis

A lifetime of stress: ATF6 in development and homeostasis

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

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