转录基因分析揭示了ADNP综合征中的未折叠蛋白质反应
Anna Bieluszewska1,2, Phillip Wulfridge1,2, Kuo-Chen Fang1,2
1Genome Regulation and Cell Signaling Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Molecular and cellular biology
|February 14, 2025
概括
活动依赖神经保护蛋白 (ADNP) 的突变导致ADNP综合征. 截断的ADNP蛋白导致ER压力和神经发育受损,这表明UPR激活是疾病严重程度的潜在生物标志物.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 细胞生物学 细胞生物学
背景情况:
- 染色体调节器在自闭症谱系障碍 (ASD) 中经常发生突变.
- 由于活动依赖神经保护蛋白 (ADNP) 的突变引起的ADNP综合征,导致智力缺陷和发育迟缓.
- 在ADNP综合征病原体的基础机制仍然在很大程度上不清楚.
研究的目的:
- 研究ADNP突变对基因表达和神经差异化的功能后果,使用患者衍生的诱导多能干细胞 (iPSC).
- 在ADNP综合征中探索内细胞网膜 (ER) 应激和未折叠蛋白质反应 (UPR) 的作用.
主要方法:
- 从ADNP综合征患者中生成iPSC.
- 对突变ADNP蛋白的亚细胞局部化的分析.
- 转录造型,以评估基因表达变化.
- 评估神经分化和细胞存活.
- 测量ER压力标志物和UPR激活.
主要成果:
- ADNP突变可以导致异常细胞下定位的截断ADNP蛋白.
- 在所有测试的ADNP突变体中观察到广泛的转录放松.
- 带有截断ADNP片段的突变体表现出ER压力,由UPR激活证明.
- 更高的UPR激活与更严重的神经分化和生存缺陷相关.
结论:
- 截断的ADNP蛋白可能会诱导ER压力,导致ADNP综合征病理.
- UPR激活可以作为ADNP综合征严重程度的潜在生物标志物.
- 这一发现可能会扩展到其他由突变导致截断蛋白质引起的ASD.
更多相关视频
10:51Consensus Brain-derived Protein, Extraction Protocol for the Study of Human and Murine Brain Proteome Using Both 2D-DIGE and Mini 2DE Immunoblotting
Published on: April 10, 2014
16.0K
04:22Author Spotlight: Exploring Sex-Specific Glial Signatures and Therapeutic Leads for Alzheimer's Disease
Published on: May 20, 2024
749
相关概念视频
01:37The Unfolded Protein Response
4.4K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.4K
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
02:27Nonsense-mediated mRNA Decay
10.4K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.4K