Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes.
Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes.
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DOI：
10.1007/s12192-018-0897-y
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发表时间：
2018-09
影响因子：
3.8
通讯作者：
de Belleroche J
中科院分区：
文献类型：
--
作者：
Montibeller L;de Belleroche J
内质网（ER）通过未折叠蛋白反应（UPR）在维持蛋白质稳态方面发挥着重要作用，该反应在大多数神经退行性疾病中被强烈激活。由 IRE1α 和 ATF6 介导的 UPR 信号通路通过一系列转录因子的反式激活在维持 ER 稳态中发挥着至关重要的作用。当激活时，这些转录因子诱导参与蛋白质折叠和降解的基因表达，具有促生存作用。然而，这些转录因子对不同神经退行性疾病的具体贡献仍不清楚。在这里，我们表征了受 XBP1 和 ATF6 强烈影响的 44 个靶基因，并量化了肌萎缩侧索硬化症 (ALS) 病例死后脊髓中以及额颞叶变性 (FTLD) 和阿尔茨海默病 (AD) 病例和对照的额叶和颞叶皮层中基因子集的表达。我们发现 IRE1α-XBP1 和 ATF6 通路在 ALS 和 AD 中均被强烈激活。在 ALS 中，XBP1 和 ATF6 的激活通过已知和新靶基因（特别是参与共伴侣活性和 ER 相关降解 (ERAD)）（例如 DNAJB9、SEL1L 和 OS9）表达的大幅增加得到证实。在 AD 病例中，出现了一种独特的模式，其中参与蛋白质折叠的靶标更为突出，例如 CANX、PDIA3 和 PDIA6。这些结果表明，IRE1α-XBP1 和 ATF6 靶基因的重叠模式和疾病特异性模式在 AD 和 ALS 中均被激活，这可能与新治疗策略的开发相关。内质网（ER）通过未折叠蛋白反应（UPR）在维持蛋白质稳态中发挥重要作用。两条主要的 UPR 信号通路由 IRE1α 和 ATF6 介导。在这里，我们证明，与阿尔茨海默氏病（AD）病例相比，这些途径激活了肌萎缩侧索硬化症（ALS）人类死后组织中的差异基因集。我们的结果确定了 IRE1α 和 ATF6 的特定靶点，这些靶点可能对新治疗策略和潜在生物标志物的开发产生重大影响。本文的在线版本 (10.1007/s12192-018-0897-y) 包含补充材料，可供授权用户使用。
The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR), which is strongly activated in most neurodegenerative disorders. UPR signalling pathways mediated by IRE1α and ATF6 play a crucial role in the maintenance of ER homeostasis through the transactivation of an array of transcription factors. When activated, these transcription factors induce the expression of genes involved in protein folding and degradation with pro-survival effects. However, the specific contribution of these transcription factors to different neurodegenerative diseases remains poorly defined. Here, we characterised 44 target genes strongly influenced by XBP1 and ATF6 and quantified the expression of a subset of genes in the human post-mortem spinal cord from amyotrophic lateral sclerosis (ALS) cases and in the frontal and temporal cortex from frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) cases and controls. We found that IRE1α-XBP1 and ATF6 pathways were strongly activated both in ALS and AD. In ALS, XBP1 and ATF6 activation was confirmed by a substantial increase in the expression of both known and novel target genes involved particularly in co-chaperone activity and ER-associated degradation (ERAD) such as DNAJB9, SEL1L and OS9. In AD cases, a distinct pattern emerged, where targets involved in protein folding were more prominent, such as CANX, PDIA3 and PDIA6. These results reveal that both overlapping and disease-specific patterns of IRE1α-XBP1 and ATF6 target genes are activated in AD and ALS, which may be relevant to the development of new therapeutic strategies. The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR). Two major UPR signalling pathways are mediated by IRE1α and ATF6. Here, we demonstrate that these pathways activate differential gene sets in human post-mortem tissues derived from amyotrophic lateral sclerosis (ALS) compared to Alzheimer’s disease (AD) cases. Our results identify IRE1α and ATF6 specific targets that can have major implications in the development of new therapeutic strategies and potential biomarkers. The online version of this article (10.1007/s12192-018-0897-y) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
Katayama, T;Imaizumi, K;Tohyama, M
通讯作者：
Tohyama, M
影响因子：
9.8
作者：
Dombroski, Beth A.;Nayak, Renuka R.;Spielman, Richard S.
通讯作者：
Spielman, Richard S.
影响因子：
1.5
作者：
Adachi, Yusuke;Yamamoto, Keisuke;Mori, Kazutoshi
通讯作者：
Mori, Kazutoshi
影响因子：
25
作者：
de L'Etang, Audrey Filezac;Maharjan, Niran;Saxena, Smita
通讯作者：
Saxena, Smita
哺乳动物转录因子 ATF6 以跨膜蛋白的形式合成，并在内质网应激时通过蛋白水解激活
影响因子：
3.3
作者：
Haze, K;Yoshida, H;Mori, K
通讯作者：
Mori, K