The Chinese Academy of Sciences has found the molecular process of aging-induced neurodegenerative diseases

neurodegenerative diseases, including Alzheimer's disease (AD), lateral sclerosis (ALS), frontal lobe dementia (FTD), are all aging-related diseases. Neurodegenerative diseases cause great pain and burden to patients and families, but there is no drug in the world that can effectively treat neurodegenerative diseases. The World Health Organization predicts that by 2040, neurodegenerative diseases will replace cancer as the second deadly disease in humans. But there is no understanding of how aging promotes neurodegenerative diseases. Therefore, the molecular structure of aging to promote neurodegenerative diseases is one of the key topics in neuroscience research.
Neurodegenerative diseases are closely related to gene mutations, but it is not clear how these genetic mutations interact with aging to induce neurodegenerative diseases, which makes it difficult to develop drugs and methods to treat neurodegenerative diseases.
Years of research by Yuan Wei's research team at the Institute of Biological and Chemical Intersectional Research of the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences have found that the activity of RIPK1 can be detected in mouse models of neurodegenerative diseases, as well as in human samples of Alzheimer's disease and lateral sclerosis of the spinal cord. At the same time, inhibiting RIPK1 activity can reduce inflammation and nerve cell death in mouse models of neurodegenerative diseases.
24, the important study was published online in the
Journal. As the founder of the field of cellular programmed death, Professor Yuan Has long been engaged in the study of the molecular mechanism of cellular programmed death and the pathogenic mechanism of neurodegenerative diseases.
, the team found the important role of RIPK1, a key regulator in the cell death signaling path, in neurodegenerative diseases. RIPK1 is one of the members of the "subject action protein kinase" family, which is responsible for the opening and regulation of important physiological processes such as apoptosis, cell necrosis and cell inflammation. The researchers found that the ALS risk gene TBK1 was able to bind directly to phosphorylation modified RIPK1 in the cell death complex, thereby inhibiting RIPK1 activation and the accompanying cellular programmed death. In the absence of TBK1, RIPK1 is released from a suppressed state, making it easier to activate and cause cell death when stimulated by tumor necrotics. This phenomenon perfectly explains the cause of death of TBK1 missing mouse embryos. When RIPK1 kinase activity is missing (RIPK1 D138N), mice with missing TBK1 survive well. RIPK1, as a key factor in the regulation of death signals, is regulated by a variety of proteins.
analysis, the researchers found an interesting phenomenon, that is, another RIBK1 inhibitor TAK1 increased activity when TBK1 was missing, enhancing the inhibition of RIPK1, thus to some extent making up for the consequences of TBK1 deficiency.
"TBK1 gene mutations are an important factor in causing some familial ALS/FTD, but most carriers of TBK1 mutations still develop after age 60, suggesting that aging plays an important role in promoting ALS/FTD caused by TBK1 mutations. Yuan told reporters, "We focused on how aging in the absence of part of TBK1 to promote the occurrence of ALS." The changes in gene expression in the forehead cortical layer of young and old adults were analyzed, and another RIBK1 inhibitor, TAK1, was found to have a significant decrease in expression in the brains of older adults. This
suggests that aging can lead to a gradual decrease in TAK1's inhibition of RIPK1. Therefore, in the missing part of TBK1 population, the decline of TAK1 caused by aging will be superimposed with the absence of TBK1, further promoting the activity of RIPK1 leading to the occurrence of neurodegenerative diseases.
further through mouse experiments, it is found that RIPK1 activity inhibition can save all ALS/FTD disease symptoms and behavioral changes, proving that RIPK1 over-activation is the key factor of ALS/FTD disease, this discovery further proves that RIPK1 is an important target for the treatment of ALS/FTD.
Shen Yong, a professor at the University of Science and Technology of China and director of the Brain Aging and Brain Disease Research Center at the University of Science and Technology of China, believes that aging can lead to the degradation of various organ functions, including the nervous system, but does not understand how aging promotes disease at the molecular level. It is one of the leading problems in the field of neuroscience to explore the molecular mechanism of body aging, especially the key molecular regulation mechanism of brain aging to the evolution of neurodegenerative diseases. He said the study was the first to clearly explain the absence of TBK1 and the increased risk of ALS/FTD from genetic mutations, and the first to reveal the molecular pathogenesis of aging for ALS/FTD. (Source: Science Network Huang Xin)