Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome.

IF 3.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Anna Bieluszewska, Phillip Wulfridge, Kuo-Chen Fang, Yan Hong, Tomoyo Sawada, Jennifer Erwin, Hongjun Song, Guo-Li Ming, Kavitha Sarma
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引用次数: 0

Abstract

Chromatin regulators are frequently mutated in autism spectrum disorders, but in most cases how they cause disease is unclear. Mutations in the activity dependent neuroprotective protein (ADNP) causes ADNP syndrome, which is characterized by intellectual deficiency and developmental delays. To identify mechanisms that contribute to ADNP syndrome, we used induced pluripotent stem cells derived from ADNP syndrome patients as a model to test the effects of syndromic ADNP mutations on gene expression and neurodifferentiation. We found that some ADNP mutations result in truncated ADNP proteins, which displayed aberrant subcellular localization. Gene expression analyses revealed widespread transcriptional deregulation in all tested mutants. Interestingly, mutants that show presence of ADNP fragments show ER stress as evidenced by activation of the unfolded protein response (UPR). The mutants showing the greatest UPR pathway activation associated with the most severe neurodifferentiation and survival defects. Our results reveal the potential to explore UPR activation as a new biomarker for ADNP syndrome severity and perhaps also in other ASDs where mutations result in presence of truncated proteins.

转录组学分析揭示了ADNP综合征中未折叠蛋白的反应。
染色质调节因子在自闭症谱系障碍中经常发生突变,但在大多数情况下,它们是如何引起疾病的尚不清楚。活性依赖性神经保护蛋白(ADNP)的突变导致ADNP综合征,其特征是智力缺陷和发育迟缓。为了确定导致ADNP综合征的机制,我们使用来自ADNP综合征患者的诱导多能干细胞作为模型来测试综合征性ADNP突变对基因表达和神经分化的影响。我们发现一些ADNP突变导致ADNP蛋白截短,这显示出异常的亚细胞定位。基因表达分析显示,在所有测试的突变体中普遍存在转录失调。有趣的是,显示ADNP片段存在的突变体显示内质网应激,这可以通过未折叠蛋白反应(UPR)的激活来证明。显示最大UPR通路激活的突变体与最严重的神经分化和生存缺陷相关。我们的研究结果揭示了探索UPR激活作为ADNP综合征严重程度的新生物标志物的潜力,也许在其他突变导致蛋白质截短的asd中也是如此。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular and Cellular Biology
Molecular and Cellular Biology 生物-生化与分子生物学
CiteScore
9.80
自引率
1.90%
发文量
120
审稿时长
1 months
期刊介绍: Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.
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