酶缺陷,脑细胞死亡 z-bo 2020-10-16 473

　　In a healthy brain, a waste removal process called "autophagy" usually removes and destroys damaged cellular components, including malformed proteins (such as tau and toxic mitochondria). Otherwise, such cellular debris will look like uncollected The debris accumulates, causing brain cells (neurons) to die, and ultimately to the minds of patients suffering from Alzheimer's disease and certain other neurodegenerative diseases. Undermine cognitive ability. Memory and reasoning. P62 protein is a selective autophagy cargo receptor, which plays an important role in eliminating tau protein folding errors and mitochondrial dysfunction (an energy source for all cells, including neurons).

　　Currently, neuroscientists at the Bird Alzheimer's Disease Center of the University of South Florida Health (USFHealth) are the first to disrupt the ability of the phosphatase Slingshot-1 (SSH1) protein to act as an effective "garbage collector" for p62. I reported that this undermines this effect. In preclinical studies, researchers showed that the role of SSH1 in preventing p62-mediated tau protective clearance is independent of the role of SSH1 in cocoaline activation.

　　The senior author of the paper, Dr. David Kang, said: "Slingshot-1 is an important participant in the regulation of tau and neurotoxic mitochondrial levels. Therefore, it is very important to know exactly what goes wrong when it accumulates in the brain. The defect caused by the p62 pathway. A better understanding of the development of SSH1 inhibitors (drugs) to prevent or delay Alzheimer’s disease and related neurodegenerative diseases.”

　　The main author of this study is Dr. Cenxiao Fang. Those people already know that the TBK1 enzyme phosphorylates the serine 403 (SER403) site of p62 protein when removing bad mitochondria, thereby activating p62. However, no scientists have found an enzyme that can remove phosphoric acid from p62, the so-called dephosphorylation. In a series of gene inactivation and overexpression experiments using human cell lines, primary neurons, and taupacy mouse models, the authors discovered that SSH1, a dephosphorylase that specifically acts on SER403, can remove important phosphates on p62 Of enzymes. This will inactivate p62. The researchers also showed that two main and completely independent signal transduction pathways (one for p62 and one for cophyllin) related to tau pathology are regulated by the same enzyme SSH1.