在CLN1疾病模型中,有缺陷的原蛋白贩运导致了内细胞网膜压力
Nisha Plavelil1, Abhilash P Appu1, K C Gopal1
1Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America.
Neurobiology of disease
|March 30, 2025
概括
溶解体储存障碍,如CLN1疾病,由于蛋白质贩运受损,导致神经退行. 这项研究揭示了有缺陷的棕基蛋白硫酶-1 (PPT1) 破坏了ER-Golgi运输,导致ER压力和神经退行在CLN1疾病中.
科学领域:
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 溶酶体储存障碍 (LSD) 是一种遗传性代谢疾病,通常会导致神经退行.
- 一种致命的LSD,CLN1疾病是CLN1基因的突变导致的,该基因编码了棕酸蛋白 thioesterase-1 (PPT1).
- 细胞内膜网膜 (ER) 应激和未折叠蛋白质反应 (UPR) 与Cln1-/-小鼠的神经退行有关,但潜在的机制尚不清楚.
研究的目的:
- 调查PPT1缺乏与ER压力和CLN1疾病中神经退行症相关联的机制.
- 确定从ER到Golgi的受损前级蛋白贩运是否有助于ER压力.
- 探索S-palmitoylation在贩运COPII囊泡相关蛋白质中的作用.
主要方法:
- 从Cln1-/-和野生型 (WT) 鼠皮质组织中对ER分量的比较分析.
- 在ER分数中对COPII囊泡相关蛋白质的量化.
- 研究COPII蛋白和CLN8.8的S-棕化状态.
- 评估ER-Golgi在缺乏Ppt1模型中的CLN8和其他蛋白质的贩运.
主要成果:
- 在Cln1-/-小鼠的ER中,多个COPII囊泡相关蛋白质 (Sar1,Sec23,Sec24,Sec13,Sec31) 的水平显著升高.
- 大多数COPII蛋白质,除Sec13外,都是S-palmitoylation的目标,这是PPT1介导的过程.
- PPT1 缺陷影响了 CLN8 和其他 COPII 相关蛋白质的 ER-Golgi 贩运.
- 损坏的前进性贩运导致了ER中的蛋白质积累,导致ER压力和UPR.
结论:
- 从ER到Golgi的失调的原蛋白贩运有助于CLN1疾病中的ER压力.
- 缺少PPT1会破坏参与COPII囊泡形成和功能的关键蛋白质的S-palmitoylation和贩运.
- 这种ER-蛋白停滞和随后的ER-压力/UPR是推动CLN1疾病神经退行的机制.
相关概念视频
01:17Role of ER in the Secretory Pathway
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
01:45ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
01:37The Unfolded Protein Response
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...
01:27Post-translational Translocation of Proteins to the RER
A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
01:31Regulation of the Unfolded Protein Response
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...