[이데일리 강민구 기자] The Institute for Basic Science (IBS) announced that a research team led by Nanomedicine Research Fellow Cheon Jin-woo director and Research Fellow Min-seok Kwak, together with California State University professor Young-wook Jeon, discovered the Notch receptor activation signaling process that plays an important role in tissue development and in the formation process of beta-amyloid known to cause Alzheimer’s.
Notch signaling is an important cell-cell interaction that regulates cell division and neuronal development. Incorrect Notch signals cause various diseases. Amyloid-beta, which is formed from the amyloid precursor protein, accumulates in tissues, causes nerve damage and is involved in the development of Alzheimer’s disease.
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The activation of Notch and the formation of amyloid-beta occur through the sequential cleavage of the Notch receptor, the amyloid precursor protein, by two different types of enzymes in the cell membrane. Relatively little is known about the molecular mechanisms by which these processes are finely regulated spatiotemporally and about the substrate specificity of enzymes.
The research team confirmed that adhesive synapses, a structure that controls the junctions between cells, act as a spatial switch that determines the order of sequential cleavage processes and is required for normal Notch signal control. It was also found that the Notch receptor-ligand interaction (substance that binds to the receptor and regulates its activity) and the first cleavage process of the receptor occur outside the structure of the adhesive junction and the second cleavage process occurs within the structure of the adhesive joint.
During the study, using “mechanogenetics”, a nanotechnology capable of providing mechanical and spatiotemporal stimuli to specific receptors, the adhesive junctions recruit gamma secretase enzymes at high concentrations and access the Notch receptors that have not undergone the first cleavage process. also confirmed that the block
It turned out that the Notch signal was not activated when the expression of the protein cadherin was knocked out by current gene-editing technology. When cadherin expression was suppressed in neural stem cells in the developing mouse brain, the stem cells differentiated into neurons abnormally rapidly. This demonstrates that the process of Notch signal control by adhesive junctions is involved in the development of the nervous system.
The research team also found that when the formation of adhesive junctions was inhibited in cells expressing amyloid precursor protein, the amount of amyloid beta formed was reduced. He showed that the formation of amyloid-beta, known as the main cause of Alzheimer’s disease, can be inhibited by controlling the protein cleavage process.
Professor Jeon Young-wook said: ‘For the first time, we have suggested the molecular and cellular mechanisms of the sequential cleavage of proteins required for Notch signaling activation and beta-amyloid formation.’ Researcher Min-Seok Kwak also said, “We expect to contribute to cancer research through abnormal cell signal transmission and Alzheimer’s disease treatment research through inhibition of beta-amyloid formation.”
The research results were published online on December 2 last year in the international journal Nature Cell Biology.
