Mechanogenetics technology reveals the process of tissue development and amyloid beta production
| ▲ Molecular mechanism of Notch signal activation (photo = courtesy of IBS) |
[메디컬투데이=김동주 기자] Center for Basic Science (IBS) Center for Nanomedicine, Director Jinwoo Cheon (Professor, Department of Chemistry, School of Advanced Sciences, Yonsei University), Research Fellow Minseok Kwak (Professor, Institute for Advanced Study, Yonsei University), and the research team collaborated with California State University (UCSF) Professor Younguk Jeon (Visiting Professor, Center for Nanomedicine Research) to develop nanotechnology and cell engineering technology were used to identify the Notch receptor signal activation process, which plays an important role in tissue development, and the formation mechanism of amyloid-beta (Aβ), known as the main cause of Alzheimer’s disease.
Notch signaling has been known to be an important cell-to-cell interaction regulating cell division and neuronal development. Faulty Notch signaling is a direct cause of various diseases, especially cancer. In addition, amyloid beta formed from amyloid precursor protein (APP) accumulates in tissues, causes nerve damage, and is known to be involved in the development of Alzheimer’s disease.
Interestingly, both Notch activation and amyloid beta formation occur through sequential proteolysis of Notch receptors and amyloid precursor proteins by two different types of enzymes present in cell membranes. Therefore, identifying the factors of this cutting process and understanding the control mechanisms are very important for understanding essential life phenomena such as stem cell and tissue development, and for preventing and treating diseases such as cancer and Alzheimer’s.
However, relatively little is known about the molecular mechanism by which the sequential cleavage process is precisely controlled spatiotemporally and the substrate specificity of enzymes.
The research team found that Adherens junctions (AJ), structures that control junctions between cells, act as a spatial switch that determines the sequence of sequential cleavage processes and are essential for normal Notch signal control.
In particular, it was found that the Notch receptor-ligand (substance that binds to the receptor and regulates its activity) interaction and the first cleavage process of the receptor occur outside the junction structure, and the second cleavage process occurs within the junction structure.
Before activation, the size of the Notch receptor is greater than the width of the adhesive junction, limiting access to the adhesive junction. The Notch receptor, which binds to the ligand and initiates activation, is cleaved by the ADAM enzyme outside the adhesive junction structure, and the reduced size receptor approaches the adhesive junction. Soon after, the Notch receptor that entered the adhesive junction undergoes a second cleavage process by the γ-secretase enzyme recruited at high concentrations therein, leading to activation of signal transduction.
The research team uses Mechanogenetics nanotechnology, which can deliver mechanical, spatiotemporal stimuli to specific receptors, by recruiting high concentrations of gamma secretase enzyme to adhesive junctions and allowing access to Notch receptors that have not undergone the first cleavage process. confirmed blocking. In other words, it was confirmed that adhesive junctions function to prevent abnormal receptor-enzyme interactions and Notch activation.
To confirm this, it was confirmed that the Notch signal was not activated when the CRISPR-Cas gene editing technology was used to remove the expression of Cadherin protein, which plays a key role in maintaining the mutual adhesion between cells by forming adhesive junction structures. .
In addition, when cadherin expression was suppressed in neural stem cells in the developing mouse brain, the stem cells differentiated into neurons abnormally quickly. As a result, it was confirmed that the process of controlling the Notch signal by adhesive junctions is involved in the development of the nervous system.
Furthermore, it was found that when the formation of adhesive junctions was inhibited in cells expressing the amyloid precursor protein, the amount of amyloid beta formed was reduced. By controlling the protein cleavage process, it was shown that the formation of amyloid beta, known as the main cause of Alzheimer’s, can be suppressed.
Professor Jeon Young-wook said, “For the first time, we have presented a new molecular and cytological mechanism of the sequential cleavage process of proteins required for Notch signal activation and amyloid beta formation.” This is the result of successfully using the developed mechanogenetics nanotechnology for cell signaling research.”
Research Fellow Min-Seok Kwak said, “This research is expected to greatly contribute to cancer-related research by abnormal cell signal transmission and research on the treatment of Alzheimer’s disease through inhibition of amyloid beta formation in the future.” We plan to expand our research with the development of brain organoids.”
Meanwhile, the results of this research were published online on December 2, 2022 in the international journal Nature Cell Biology (IF 28.82).
Medical Today Reporter Kim Dong-ju (ed30109@mdtoday.co.kr)
[저작권자ⓒ 메디컬투데이. 무단전재-재배포 금지]