Mechanogenetics technology reveals the process of tissue development and beta-amyloid 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 was used to identify the Notch receptor signaling 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 is known to be an important cell-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 the sequential proteolysis of Notch receptors and amyloid precursor proteins by two different types of enzymes found in cell membranes. Therefore, identifying the drivers of this shearing 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 about the substrate specificity of enzymes.
The research team found that Adherens junctions (AJs), structures that control the junctions between cells, act as a spatial switch that determines the sequence of sequential cleavage processes and are essential for normal Notch signaling control.
In particular, it has been found that the Notch receptor-ligand interaction (substance that binds to the receptor and regulates its activity) and the first process of cleavage of the receptor take place outside the junction structure, while the second process Cleavage occurs within the joint structure.
Prior to 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 small-sized receptor approaches the adhesive junction. Soon after, the Notch receptor that has entered the adhesive junction undergoes a second cleavage process by the enzyme γ-secretase recruited at high concentrations within it, which leads to the activation of signal transduction.
The research team uses Mechanogenetics nanotechnology, which can deliver mechanical and spatiotemporal stimuli to specific receptors, recruiting high concentrations of the gamma secretase enzyme to the adhesive junctions and allowing access to Notch receptors that have not undergone the first cleavage process. In other words, the adhesive junctions have been confirmed to function to prevent abnormal receptor-enzyme interactions and activation of Notch.
In confirmation of this, it was confirmed that the Notch signal was not activated when the expression of the protein cadherin was removed, which plays an important role in maintaining the mutual adhesion between cells by forming adhesive junction structures with the technology of CRISPR-Cas gene editing.
Furthermore, when cadherin expression in neural stem cells in the developing mouse brain was suppressed, the stem cells differentiated into neurons abnormally rapidly. Consequently, the process of controlling the Notch signal by adhesive junctions has been confirmed to be involved in the development of the nervous system.
Furthermore, it was found that when the formation of adhesive junctions was inhibited in cells expressing amyloid precursor protein, the amount of amyloid-beta formed was reduced. By controlling the protein cleavage process, it has been shown that the formation of beta amyloid, known to be a major cause of Alzheimer’s disease, can be suppressed.
Professor Jeon Young-wook said: ‘For the first time, we have presented a novel molecular and cytological mechanism of the sequential cleavage process of proteins required for Notch signal activation and beta-amyloid formation.’ . nanotechnology for cell signaling research”.
Researcher Min-Seok Kwak said, “This research is expected to greatly contribute to cancer research through abnormal cell signal transmission and Alzheimer’s disease treatment research through inhibition of beta-amyloid formation in the future.” . 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]
